VCV000012143.125 - ClinVar

NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(56)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)

Variation ID: 12143 Accession: VCV000012143.125

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.2 11: 66526181 (GRCh38) [ NCBI UCSC ] 11: 66293652 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 20, 2014	Oct 20, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024649.5:c.1169T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078925.3:p.Met390Arg	missense
NM_001348571.2:c.*21+755A>C		intron variant
NC_000011.10:g.66526181T>G
NC_000011.9:g.66293652T>G
NG_009093.1:g.20534T>G
	Q8NFJ9:p.Met390Arg

... more HGVS ... less HGVS

Protein change

M390R

Other names

NP_078925.3:p.(Met390Arg)

Canonical SPDI

NC_000011.10:66526180:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00100 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00100

Exome Aggregation Consortium (ExAC) 0.00148

The Genome Aggregation Database (gnomAD), exomes 0.00151

Trans-Omics for Precision Medicine (TOPMed) 0.00210

The Genome Aggregation Database (gnomAD) 0.00212

Links

ClinGen: CA223760 UniProtKB: Q8NFJ9#VAR_017216 OMIM: 209901.0001 dbSNP: rs113624356 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BBS1		-	-	GRCh38 GRCh37	454	1124
ZDHHC24	-	-	-	GRCh38 GRCh37	14	682

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Bardet-Biedl syndrome 1	Pathogenic/Likely pathogenic (25)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000012926.74
not provided	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000082202.54
Retinal dystrophy	Pathogenic (3)	criteria provided, single submitter	Aug 15, 2019	RCV000210319.14
Retinitis pigmentosa	Pathogenic/Likely pathogenic (3)	no assertion criteria provided	Jun 23, 2019	RCV000504693.13
Bardet-Biedl syndrome	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000174408.40
See cases	Pathogenic (1)	criteria provided, single submitter	Oct 15, 2021	RCV002251900.9
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 6, 2021	RCV002513000.9
BBS1-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 13, 2024	RCV003390672.6
Usher syndrome	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787785.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 19, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000246778.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (May 09, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000280850.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Pathogenic (Aug 04, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699512.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018	Publications: PubMed (9) PubMed: 12524598‚ 18032602‚ 20498079‚ 17980398‚ 12118255‚ 18766993‚ 18669544‚ 12837689‚ 12677556 Comment: Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant … (more) Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Met390 is conserved across vertebrates and is located in the Quinoprotein alcohol dehydrogenase-like superfamily domain. An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).This variant is the most common BBS-causing mutation, explaining nearly 80% of all BBS patients (Davis_PNAS_2007), and was found in 182/121966 control chromosomes. The variant is commonly found in homozygous state in BBS patients, but has also been reported in compound heterozygous patients. It has been suggested that variants in other BBS genes (i.e. BBS2, BBS6, etc) may act as a severity modifier.In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known disease variant and has been classified as pathogenic. (less)
Pathogenic (May 22, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225702.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BBS1 Number of individuals with the variant: 17 Sex: mixed
Pathogenic (Jun 17, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Bardet-Biedl syndrome (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712198.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (8) PubMed: 12524598‚ 12677556‚ 18032602‚ 22940089‚ 12837689‚ 27032803‚ 12118255‚ 15314642 Comment: The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it … (more) The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beal es 2003, Badano 2003, Fan 2004, Cox 2012). This variant has also been identified in 0.27% (347/126644) of chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs113624356). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant h as been reported by other clinical laboratories in ClinVar (Variation ID: 12143) . Animal models in mice have shown that this variant causes Bardet-Biedl syndrom e (Davis 2007). In summary, this variant meets our criteria to be classified as pathogenic for Bardet-Biedl syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3; PM3_VeryStrong; PP3 (less) Number of individuals with the variant: 3
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV001156384.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020	Number of individuals with the variant: 4 Clinical Features: Rod-cone dystrophy (present) , Polydactyly (present) , Childhood-onset truncal obesity (present) , Delayed social development (present) , Curved phalanges of the toes (present) , Intellectual … (more) Rod-cone dystrophy (present) , Polydactyly (present) , Childhood-onset truncal obesity (present) , Delayed social development (present) , Curved phalanges of the toes (present) , Intellectual disability (present) , Asthma (present) , Vitamin B12 deficiency (present) (less)
Pathogenic (Aug 15, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239239.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Nov 12, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193854.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (5) PubMed: 12677556‚ 12524598‚ 21052717‚ 18032602‚ 20498079 Comment: NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and … (more) NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and 20498079. Classification of NM_024649.4(BBS1):c.1169T>G(M390R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Likely pathogenic (Feb 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: inherited	Molecular Biology Laboratory, Fundació Puigvert Study: KidneyPanel_2020 Accession: SCV001424979.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021	Publications: PubMed (1) PubMed: 33532864
Pathogenic (Dec 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448888.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 3 Clinical Features: Sacral dimple (present) , Tethered cord (present) , Arnold-Chiari type I malformation (present) , Syringomyelia (present) , Short palpebral fissure (present) , Myopia (disease) (present) … (more) Sacral dimple (present) , Tethered cord (present) , Arnold-Chiari type I malformation (present) , Syringomyelia (present) , Short palpebral fissure (present) , Myopia (disease) (present) , Hypermetropia (present) , Abnormality of dental structure (present) , Agenesis of maxillary incisor (present) , Hemangioma (present) , Hip dysplasia (present) , Joint hypermobility (present) , Rectal prolapse (present) , Renal malrotation (present) , Atrial septal defect (present) , Ventricular septal defect (present) , Bicuspid aortic valve (present) , Patent ductus arteriosus (present) , Premature thelarche (present) , Generalized hypotonia (present) , Expressive language delay (present) , Bilateral cleft lip and palate (present) , Microcephaly (present) , Conductive hearing impairment (present) , Broad nasal tip (present) , Low-set ears (present) , Full cheeks (present) , Anteverted ears (present) (less) Sex: female
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: biparental	Daryl Scott Lab, Baylor College of Medicine Accession: SCV002515296.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Publications: PubMed (1) PubMed: 36474027 Number of individuals with the variant: 1
Pathogenic (Feb 11, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV002097647.2 First in ClinVar: Feb 20, 2022 Last updated: May 20, 2023	Observation 1: Clinical Features: Hyperlipidemia (present) Secondary finding: no Observation 2: Clinical Features: Developmental regression (present) , Leukodystrophy (present) , Lower limb spasticity (present) , Absent speech (present) Secondary finding: no
Pathogenic (Dec 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017338.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bardet-Biedl syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253934.11 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 12118255‚ 12524598‚ 12677556‚ 12837689‚ 15314642‚ 22581970‚ 22940089‚ 23143442‚ 27032803‚ 18032602‚ 20498079 Comment: This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). … (more) This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). This variant is present in population databases (rs113624356, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome and accounts for approximately 80% of BBS1 variants. It has also been observed in individual(s) with non-syndromic retinitis pigmentosa (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22581970, 22940089, 23143442, 27032803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 06, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003539679.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 12118255‚ 12524598‚ 12677556‚ 18032602‚ 20498079‚ 22998390‚ 23143442‚ 23565731‚ 27032803 Comment: The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution … (more) The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution at nucleotide position 1169, causing the methionine (M) at amino acid position 390 to be replaced by an arginine (R). The p.M390R alteration is the most common pathogenic alteration in BBS1 and has been identified in numerous homozygous and compound heterozygous individuals with Bardet-Biedl syndrome (BBS) (Mykytyn, 2002; Estrada-Cuzcano, 2012; Charkoudian, 2013) as well as in compound heterozygous individuals with retinal dystrophies (Bravo-Gil, 2016). Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010). In addition, homozygous knock-in mice with this mutation demonstrated a phenotype similar to human BBS (Davis, 2007). Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000807645.3 First in ClinVar: Oct 05, 2015 Last updated: Jun 17, 2024	Publications: PubMed (1) PubMed: 25326635
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611250.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Jun 25, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: Broad Institute Center for Mendelian Genomics (CMG) Accession: SCV000693896.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018	Number of individuals with the variant: 1 Clinical Features: Polycystic kidney disease (present) , Biliary atresia (present) , Gastrointestinal malrotation (present) , Congenital heart disease (present)
Pathogenic (Jun 02, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BARDET-BIEDL SYNDROME 1 Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996152.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Comment: This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in … (more) This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.16% (436/276714); no homozygotes are present in gnomAD. The c.1169T>G (p.Met390Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Nov 01, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001143152.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (10) PubMed: 12118255‚ 12524598‚ 12677556‚ 12837689‚ 17980398‚ 29264490‚ 18032602‚ 22940089‚ 23143442‚ 27659767 Comment: The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least … (more) The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome Affected status: no Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251519.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 Comment: carrier finding	Publications: PubMed (6) PubMed: 12118255‚ 12677556‚ 23143442‚ 22581970‚ 22940089‚ 27032803 Comment: The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state … (more) The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state in an individual with non-syndromic retinitis pigmentosa (PMID: 12118255; 12677556; 23143442; 22581970; 22940089; 27032803). (less) Number of individuals with the variant: 1
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573536.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (5) PubMed: 18032602‚ 20498079‚ 23943788‚ 12524598‚ 12677556 Comment: The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PS3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760275.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002058656.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Publications: PMID:23143442 PMID:23143442 PMID:12118255 PMID:12118255 PMID:22940089 PMID:22940089 PMID:12677556 PMID:12677556 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23143442, 22940089, 12677556, 12118255, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.662, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001570, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Night blindness (present) , Peripheral visual field loss (present) , Retinal detachment (present)
Pathogenic (Jan 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: inherited	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002072576.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 Comment: also identified in affected sister	Comment: This variant was identified as homozygous._x000D_ Criteria applied: PM3_VSTR, PS3, PP3
Pathogenic (Oct 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002522856.1 First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022	Comment: ACMG classification criteria: PS3, PS4, PM3 Clinical Features: Renal cyst (present) , Polycystic kidney disease (present)
Pathogenic (Aug 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: inherited	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University Accession: SCV002559821.2 First in ClinVar: Feb 13, 2023 Last updated: Aug 13, 2023	Publications: DOI: doi:10.1155/2023/2564200 DOI: doi:10.1155/2023/2564200 Secondary finding: no
Pathogenic (Apr 02, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329106.9 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published … (more) One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23565731, 20498079, 25982971, 22940089, 17591906, 27032803, 22998390, 22581970, 12118255, 18032602, 23943788, 27788217, 26325558, 26022370, 23143442, 28502102, 29049287, 18766993, 30609409, 12677556, 30337596, 30718709, 28559085, 30484961, 28838317, 30614526, 31028937, 31370859, 29974258, 31456290, 12524598, 12837689, 15314642, 31980526, 32581362, 34327195, 33851411, 34383976, 33886537, 31589614, 33015405, 33369054, 32037395) (less)
Pathogenic (Feb 20, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV000373275.4 First in ClinVar: Dec 06, 2016 Last updated: Jul 22, 2023	Publications: PubMed (5) PubMed: 21642631‚ 12677556‚ 18032602‚ 12524598‚ 12118255 Comment: The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, … (more) The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, the c.1169T>G variant has been reported in a homozygous state in at least 29 families with Bardet-Biedl syndrome (BBS) and in a compound heterozygous state in at least 12 families with BBS (PMID: 12118255; 12524598; 21642631). A study also reported that the c.1169T>G variant was present in 75.7% of all families with BBS1 disease-causing variants in their US cohort and 82.6% of all families with BBS1 disease-causing variants in their UK cohort (PMID: 12677556). The c.1169T>G variant is reported in the Genome Aggregation Database at a frequency of 0.03070 in the Amish population (version 3.1.2). A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602). Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic for Bardet-Biedl syndrome. (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Bardet-Biedl syndrome Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030361.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PS4, PM2, PP3, PP5.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 2 Sex: mixed Geographic origin: Portugal
Pathogenic (Apr 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002503686.2 First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024	Publications: PubMed (8) PubMed: 12118255‚ 12524598‚ 12677556‚ 12837689‚ 18032602‚ 20498079‚ 22940089‚ 23143442 Comment: This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between … (more) This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between Methionine and Arginine. The variant is not present in a known functional domain, and the Methionine residue is moderately conserved due to gaps in the alignment for approximately two-thirds of vertebrates assessed (100 vertebrates, UCSC). It is present in a large population cohort at a frequency of 0.2% (rs113624356, 444/282,790 alleles in gnomAD v2.1). This missense accounts for ~80% of BBS1 disease-associated alleles and ~30% of all Bardet-Biedl syndrome (BBS). It has been identified homozygous or compound heterozygous with a second pathogenic variant in BBS1 in a large number of clinically diagnosed BBS cases (PMID: 12118255, 12524598), and segregates with disease in multiple families (PMID: 12677556, 12837689). The phenotype of variant carriers varies from non-syndromic retinitis pigmentosa, mild forms of BBS, to classical BBS (PMID: 22940089, 23143442). A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Bardet-Biedl syndrome 1 Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052034.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 1 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769204.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 20301537 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (444 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been seen in many individuals with Bardet-Biedl syndrome in both homozygous and compound heterozygous states (ClinVar, DECIPHER). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248424.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: BBS1: PM3:Very Strong, PP1:Strong, PM2:Supporting, PP3, PS3:Supporting Number of individuals with the variant: 17
Pathogenic (Oct 01, 2013)	no assertion criteria provided Method: literature only	BARDET-BIEDL SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033167.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 20, 2014	Publications: PubMed (5) PubMed: 12118255‚ 12524598‚ 12677556‚ 15314642‚ 23847139 Mykytyn, K. Personal Communication. (more...) Mykytyn, K. Personal Communication. 2002. Iowa City, Iowa Comment on evidence: Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the BBS1 gene in affected members of a consanguineous Puerto Rican family with Bardet-Biedl syndrome … (more) Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the BBS1 gene in affected members of a consanguineous Puerto Rican family with Bardet-Biedl syndrome (BBS1; 209900). The substitution results from a T-to-G transversion at nucleotide 1169 (1169T-G) in exon 12 (Mykytyn, 2002). Two other Puerto Rican families carried this mutation and the glu549-to-ter mutation (209901.0002) in compound heterozygosity. Mykytyn et al. (2002) found the M390R mutation in 22 of 60 unrelated North American probands with Bardet-Biedl syndrome of mostly northern European ancestry. Sixteen of the 22 individuals were homozygous for the variant (allele frequency = 0.32). Mykytyn et al. (2003) found that the M390R mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. Beales et al. (2003) identified homozygous M390R alleles in asymptomatic individuals in 2 separate families. They interpreted this as consistent with an oligogenic rather than a recessive model of disease transmission, as seen in triallelic inheritance. Fan et al. (2004) reported the cases of 2 sisters homozygous for the M390R mutation. One sister, who was also heterozygous for a G169A mutation in the BBS3 gene (600151.0002), was more severely affected than the sister without the additional mutation, suggesting a modifying effect of the mutation in BBS3. In a 53-year-old woman with 'juvenile retinitis pigmentosa-like' retinal features consistent with those seen in other BBS1 patients, but who had no syndromic features, Wang et al. (2013) identified homozygosity for the M390R mutation in the BBS1 gene. The authors stated that the mutation segregated with disease in the family, and noted that such patients should be followed for the potential development of syndromic phenotypes. (less)
Pathogenic (Jan 30, 2015)	no assertion criteria provided Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals Accession: SCV000259109.1 First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016	Publications: PubMed (1) PubMed: 26872967
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598855.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 12118255 Observation 1: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: NA Observation 2: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: NA Observation 3: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European Observation 4: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Observation 5: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinal dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598856.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 12118255 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Usher syndrome Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926794.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001454320.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807269.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742151.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959754.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (May 10, 2023)	no assertion criteria provided Method: research	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: maternal	Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago Accession: SCV003926566.1 First in ClinVar: May 27, 2023 Last updated: May 27, 2023
Pathogenic (Sep 13, 2024)	no assertion criteria provided Method: clinical testing	BBS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120938.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants … (more) The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants identified in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255). This variant is reported in 0.28% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as a founder variant in individuals of European ancestry (Estrada-Cuzcano et al. 2012. PubMed ID: 23143442). In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079). This variant has been reported in the compound heterozygous and homozygous state in individuals with Bardet-Biedl syndrome (Internal Data, PreventionGenetics). This variant is interpreted as pathogenic. (less)
Pathogenic (Sep 01, 2016)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: unknown, inherited	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804595.2 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015	Observation 1: Number of individuals with the variant: 3 Observation 2: Number of individuals with the variant: 1
Pathogenic (Sep 15, 2018)	no assertion criteria provided Method: provider interpretation	Bardet-Biedl syndrome Affected status: yes Allele origin: germline	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University Study: French fetal BBS cohort Accession: SCV000839548.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Publications: PubMed (1) PubMed: 30614526 Age: 5-8 months gestation Ethnicity/Population group: Caucasian
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160905.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
Pathogenic (Oct 25, 2018)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome Affected status: yes Allele origin: unknown	Sydney Genome Diagnostics, Children's Hospital Westmead Accession: SCV001449189.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of … (more) This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of 0.27%. p.Met390Arg has been reported to be the most frequent cause of Bardet-Biedl syndrome (Mykytyn et al.Nature Genet 2002;31:435-438). (less) Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922626.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929199.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: phenotyping only	Bardet-Biedl syndrome 1 Affected status: yes Allele origin: germline	GenomeConnect, ClinGen Accession: SCV001423443.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormality of vision (present) , Myopia (disease) (present) , Abnormal retinal morphology (present) , Arrhythmia (present) , Abnormality of cardiovascular system morphology (present) , Abnormal … (more) Abnormality of vision (present) , Myopia (disease) (present) , Abnormal retinal morphology (present) , Arrhythmia (present) , Abnormality of cardiovascular system morphology (present) , Abnormal renal morphology (present) , Misalignment of teeth (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-10-03 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Bardet-Biedl syndrome Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228911.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Hypermetropia (present) , Abnormality of vision (present) , Myopia (present) , Abnormal retinal morphology (present) Indication for testing: Diagnostic Age: 30-39 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2021-01-28 Testing laboratory interpretation: Pathogenic
Pathogenic (Apr 01, 2018)	Flagged submission flagged submission Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000926502 appears to (...more) Source: NCBI	not provided Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926502.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	Flagged submission flagged submission Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000926503 appears to (...more) Source: NCBI	Bardet-Biedl syndrome Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926503.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	Flagged submission flagged submission Method: research Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000926793 appears to (...more) Source: NCBI	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926793.2 First in ClinVar: Jul 22, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
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Comment:

Variant summary: The BBS1 c.1169T>G (p.Met390Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). Met390 is conserved across vertebrates and is located in the Quinoprotein alcohol dehydrogenase-like superfamily domain. An in vivo BBS mouse model shows that mice homozygous for the M390R mutation recapitulate aspects of the human phenotype, including retinal degeneration, male infertility, and obesity (Davis_PNAS_2007).This variant is the most common BBS-causing mutation, explaining nearly 80% of all BBS patients (Davis_PNAS_2007), and was found in 182/121966 control chromosomes. The variant is commonly found in homozygous state in BBS patients, but has also been reported in compound heterozygous patients. It has been suggested that variants in other BBS genes (i.e. BBS2, BBS6, etc) may act as a severity modifier.In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is a commonly known disease variant and has been classified as pathogenic.

Comment:

The p.Met390Arg variant in BBS1 has been identified in >50 individuals with Bard et-Biedl syndrome both in the homozygous and compound heterozygous states and it is the most common pathogenic variant in BBS1 (Mykytyn 2002; Mykytyn 2003, Beal es 2003, Badano 2003, Fan 2004, Cox 2012). This variant has also been identified in 0.27% (347/126644) of chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs113624356). Although this variant ha s been seen in the general population, its frequency is low enough to be consist ent with a recessive carrier frequency for Bardet-Biedl syndrome. This variant h as been reported by other clinical laboratories in ClinVar (Variation ID: 12143) . Animal models in mice have shown that this variant causes Bardet-Biedl syndrom e (Davis 2007). In summary, this variant meets our criteria to be classified as pathogenic for Bardet-Biedl syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3; PM3_VeryStrong; PP3

Comment:

NM_024649.4(BBS1):c.1169T>G(M390R) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS1-related. Sources cited for classification include the following: PMID 12677556, 12524598, 21052717, 18032602 and 20498079. Classification of NM_024649.4(BBS1):c.1169T>G(M390R) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 390 of the BBS1 protein (p.Met390Arg). This variant is present in population databases (rs113624356, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Bardet-Biedl syndrome and accounts for approximately 80% of BBS1 variants. It has also been observed in individual(s) with non-syndromic retinitis pigmentosa (PMID: 12118255, 12524598, 12677556, 12837689, 15314642, 22581970, 22940089, 23143442, 27032803). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS1 function (PMID: 15314642, 18032602, 20498079). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1169T>G (p.M390R) alteration is located in exon 12 (coding exon 12) of the BBS1 gene. This alteration results from a T to G substitution at nucleotide position 1169, causing the methionine (M) at amino acid position 390 to be replaced by an arginine (R). The p.M390R alteration is the most common pathogenic alteration in BBS1 and has been identified in numerous homozygous and compound heterozygous individuals with Bardet-Biedl syndrome (BBS) (Mykytyn, 2002; Estrada-Cuzcano, 2012; Charkoudian, 2013) as well as in compound heterozygous individuals with retinal dystrophies (Bravo-Gil, 2016). Functional studies in zebrafish lacking BBS1 and co-injected with wildtype mRNA and this mutation demonstrated only a partial rescue, consistent with a possible hypomorphic effect of this variant (Zaghloul, 2010). In addition, homozygous knock-in mice with this mutation demonstrated a phenotype similar to human BBS (Davis, 2007). Based on the available evidence, this alteration is classified as pathogenic.

Comment:

This variant has been previously reported as a homozygous change in patients with Bardet-Biedl syndrome 1 (PMID: 12118255, 18766993, 22998390, 27032803). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.16% (436/276714); no homozygotes are present in gnomAD. The c.1169T>G (p.Met390Arg) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic.

Comment:

The best available variant frequency is higher than the disease allele frequency. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.

Comment:

The BBS1 c.1169T>G (p.M390R) variant has been observed in the homozygous and compound heterozygous state in Bardet-Biedl syndrome (BBS), and in the compound heterozygous state in an individual with non-syndromic retinitis pigmentosa (PMID: 12118255; 12677556; 23143442; 22581970; 22940089; 27032803).

Comment:

The BBS1 c.1169T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PS3, PP1, PP5. Based on this evidence we have classified this variant as Pathogenic.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012143, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23143442, 22940089, 12677556, 12118255, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.662, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001570, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

One of the most common pathogenic BBS1 variants, accounting for 18% of the pathogenic BBS1 variants identified in one cohort (Beales et al., 2003); Published functional studies demonstrate a damaging effect as mice homozygous for the M390R variant develop cilia defects, ventriculomegaly, retinopathy, and obesity (Davis et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23565731, 20498079, 25982971, 22940089, 17591906, 27032803, 22998390, 22581970, 12118255, 18032602, 23943788, 27788217, 26325558, 26022370, 23143442, 28502102, 29049287, 18766993, 30609409, 12677556, 30337596, 30718709, 28559085, 30484961, 28838317, 30614526, 31028937, 31370859, 29974258, 31456290, 12524598, 12837689, 15314642, 31980526, 32581362, 34327195, 33851411, 34383976, 33886537, 31589614, 33015405, 33369054, 32037395)

Comment:

The BBS1 c.1169T>G (p.Met390Arg) missense variant results in the substitution of methionine at amino acid position 390 with arginine. Across a selection of available literature, the c.1169T>G variant has been reported in a homozygous state in at least 29 families with Bardet-Biedl syndrome (BBS) and in a compound heterozygous state in at least 12 families with BBS (PMID: 12118255; 12524598; 21642631). A study also reported that the c.1169T>G variant was present in 75.7% of all families with BBS1 disease-causing variants in their US cohort and 82.6% of all families with BBS1 disease-causing variants in their UK cohort (PMID: 12677556). The c.1169T>G variant is reported in the Genome Aggregation Database at a frequency of 0.03070 in the Amish population (version 3.1.2). A homozygous knock-in mouse line carrying the Met390Arg variant showed a phenotype that included retinal degeneration, male infertility, and obesity (PMID: 18032602). Based on the available evidence, the c.1169T>G (p.Met390Arg) variant is classified as pathogenic for Bardet-Biedl syndrome.

Comment:

This sequence change is predicted to replace Methionine with Arginine at codon 390 of the BBS1 protein, p.(Met390Arg). There is a moderate physicochemical difference between Methionine and Arginine. The variant is not present in a known functional domain, and the Methionine residue is moderately conserved due to gaps in the alignment for approximately two-thirds of vertebrates assessed (100 vertebrates, UCSC). It is present in a large population cohort at a frequency of 0.2% (rs113624356, 444/282,790 alleles in gnomAD v2.1). This missense accounts for ~80% of BBS1 disease-associated alleles and ~30% of all Bardet-Biedl syndrome (BBS). It has been identified homozygous or compound heterozygous with a second pathogenic variant in BBS1 in a large number of clinically diagnosed BBS cases (PMID: 12118255, 12524598), and segregates with disease in multiple families (PMID: 12677556, 12837689). The phenotype of variant carriers varies from non-syndromic retinitis pigmentosa, mild forms of BBS, to classical BBS (PMID: 22940089, 23143442). A knock-in mouse model homozygous for p.Met390Arg has cilia defects, and recapitulates aspects of the human BBS phenotype, including retinal degeneration, male infertility, and obesity (PMID: 18032602), and partial rescue (hypomorph) was demonstrated in a zebrafish assay (PMID: 20498079). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PP1_Strong, PP3.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (444 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been seen in many individuals with Bardet-Biedl syndrome in both homozygous and compound heterozygous states (ClinVar, DECIPHER). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The BBS1 c.1169T>G variant is predicted to result in the amino acid substitution p.Met390Arg. This missense variant is one of the most common pathogenic variants identified in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255). This variant is reported in 0.28% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been reported as a founder variant in individuals of European ancestry (Estrada-Cuzcano et al. 2012. PubMed ID: 23143442). In vivo and in vitro studies suggest that this variant impacts protein function (Davis et al. 2007. PubMed ID: 18032602; Zaghloul et al. 2010. PubMed ID: 20498079). This variant has been reported in the compound heterozygous and homozygous state in individuals with Bardet-Biedl syndrome (Internal Data, PreventionGenetics). This variant is interpreted as pathogenic.

Comment:

This patient is homozygous for the c.1169T>G (p.Met390Arg) variant in BBS1 gene. The p.Met390Arg is reported in dbSNP (rs113624356) with a minor allele frequency of 0.27%. p.Met390Arg has been reported to be the most frequent cause of Bardet-Biedl syndrome (Mykytyn et al.Nature Genet 2002;31:435-438).

Comment:

Variant interpretted as Pathogenic and reported on 10-03-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Comment:

Variant interpreted as Pathogenic and reported on 01-28-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
High molecular diagnostic yields and novel phenotypic expansions involving syndromic anorectal malformations.	Belanger Deloge R	European journal of human genetics : EJHG	2023	PMID: 36474027
Bardet-Biedl Syndrome Overview.	Adam MP	-	2023	PMID: 20301537
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.	Domingo-Gallego A	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2022	PMID: 33532864
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.	Mary L	Clinical genetics	2019	PMID: 30614526
Beneficial Outcomes of Sleeve Gastrectomy in a Morbidly Obese Patient With Bardet-Biedl Syndrome.	Boscolo M	Journal of the Endocrine Society	2017	PMID: 29264490
Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome.	Forsythe E	Journal of the American Society of Nephrology : JASN	2017	PMID: 27659767
Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel.	Bravo-Gil N	Scientific reports	2016	PMID: 27032803
Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.	Ellingford JM	Ophthalmology	2016	PMID: 26872967
BBS mutations modify phenotypic expression of CEP290-related ciliopathies.	Zhang Y	Human molecular genetics	2014	PMID: 23943788
Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing.	Wang X	Journal of medical genetics	2013	PMID: 23847139
Choroidal neovascularization in Bardet-Biedl syndrome.	Charkoudian LD	Ophthalmic genetics	2013	PMID: 23565731
Combining fetal sonography with genetic and allele pathogenicity studies to secure a neonatal diagnosis of Bardet-Biedl syndrome.	Ashkinadze E	Clinical genetics	2013	PMID: 22998390
BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome.	Estrada-Cuzcano A	Archives of ophthalmology (Chicago, Ill. : 1960)	2012	PMID: 23143442
Phenotypic expression of Bardet-Biedl syndrome in patients homozygous for the common M390R mutation in the BBS1 gene.	Cox KF	Vision research	2012	PMID: 22940089
A paradigm shift in the delivery of services for diagnosis of inherited retinal disease.	O'Sullivan J	Journal of medical genetics	2012	PMID: 22581970
Molecular analysis of Bardet-Biedl syndrome families: report of 21 novel mutations in 10 genes.	Chen J	Investigative ophthalmology & visual science	2011	PMID: 21642631
Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals.	Janssen S	Human genetics	2011	PMID: 21052717
Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.	Zaghloul NA	Proceedings of the National Academy of Sciences of the United States of America	2010	PMID: 20498079
A novel founder BBS1 mutation explains a unique high prevalence of Bardet-Biedl syndrome in the Faroe Islands.	Hjortshøj TD	The British journal of ophthalmology	2009	PMID: 18669544
Bardet-biedl syndrome: an atypical phenotype in brothers with a proven BBS1 mutation.	Cannon PS	Ophthalmic genetics	2008	PMID: 18766993
Retinal morphology in patients with BBS1 and BBS10 related Bardet-Biedl Syndrome evaluated by Fourier-domain optical coherence tomography.	Gerth C	Vision research	2008	PMID: 17980398
A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity.	Davis RE	Proceedings of the National Academy of Sciences of the United States of America	2007	PMID: 18032602
Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome.	Fan Y	Nature genetics	2004	PMID: 15314642
Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.	Badano JL	Human molecular genetics	2003	PMID: 12837689
Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.	Beales PL	American journal of human genetics	2003	PMID: 12677556
Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1).	Mykytyn K	American journal of human genetics	2003	PMID: 12524598
Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome.	Mykytyn K	Nature genetics	2002	PMID: 12118255
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BBS1	-	-	-	-
Mykytyn, K. Personal Communication. 2002. Iowa City, Iowa	-	-	-	-
-	-	-	-	DOI: doi:10.1155/2023/2564200
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Text-mined citations for rs113624356 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_024649.5(BBS1):c.1169T>G (p.Met390Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs113624356 ...