NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) AND Bardet-Biedl syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000174408.38

Allele description

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

Genes:

BBS1:Bardet-Biedl syndrome 1 [Gene - OMIM - HGNC]
ZDHHC24:zinc finger DHHC-type containing 24 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.2

Genomic location:

Preferred name:

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

Other names:

NP_078925.3:p.(Met390Arg)

HGVS:

NC_000011.10:g.66526181T>G
NG_009093.1:g.20534T>G
NM_001348571.2:c.*21+755A>C
NM_024649.5:c.1169T>GMANE SELECT
NM_024649.5:c.1169T>G
NP_078925.3:p.Met390Arg
NC_000011.9:g.66293652T>G
NM_024649.4:c.1169T>G
Q8NFJ9:p.Met390Arg

Protein change:

M390R; MET390ARG

Links:

UniProtKB: Q8NFJ9#VAR_017216; OMIM: 209901.0001; dbSNP: rs113624356

NCBI 1000 Genomes Browser:

rs113624356

Molecular consequence:

NM_001348571.2:c.*21+755A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_024649.5:c.1169T>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Bardet-Biedl syndrome (BBS)
Identifiers:: MONDO: MONDO:0015229; MedGen: C0752166; Orphanet: 110; OMIM: PS209900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000253934	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 12118255, 12524598, 12677556, 12837689, 22581970, 22940089, 23143442, 27032803, 15314642, 18032602, 20498079, 28492532
SCV000693896	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 25, 2017)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000699512	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 4, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12524598, 18032602, 20498079, 17980398, 12118255, 18766993, 18669544, 12837689, 12677556 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000712198	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 17, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12524598, 12677556, 18032602, 22940089, 12837689, 27032803, 12118255, 15314642, 24033266
SCV000839548	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University - French fetal BBS cohort	no assertion criteria provided	Pathogenic (Sep 15, 2018)	germline	provider interpretation	PubMed (1) [See all records that cite this PMID]
SCV001251519	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (7) [See all records that cite these PMIDs] 12118255, 12677556, 23143442, 22581970, 22940089, 27032803, 25741868
SCV001449189	Sydney Genome Diagnostics, Children's Hospital Westmead	no assertion criteria provided	Pathogenic (Oct 25, 2018)	unknown	clinical testing
SCV004030361	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 24, 2023)	germline	research	PubMed (2) [See all records that cite these PMIDs] 36909829, 25741868
SCV004228911	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	1	not provided	not provided	1	not provided	phenotyping only
not provided	germline	no	1	not provided	not provided	not provided	not provided	research
not provided	unknown	yes	3	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	1	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	germline	yes	not provided	not provided	not provided	not provided	not provided	provider interpretation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet-Biedl syndrome.

Zaghloul NA, Liu Y, Gerdes JM, Gascue C, Oh EC, Leitch CC, Bromberg Y, Binkley J, Leibel RL, Sidow A, Badano JL, Katsanis N.

Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10602-7. doi: 10.1073/pnas.1000219107. Epub 2010 May 24.

PubMed [citation]

PMID:: 20498079
PMCID:: PMC2890780

See all PubMed Citations (20)

Details of each submission

From Invitae, SCV000253934.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG), SCV000693896.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699512.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712198.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (9)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		3	not provided	3	not provided

From Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University - French fetal BBS cohort, SCV000839548.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	not provided	not provided	not provided	provider interpretation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD, SCV000926503.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251519.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (7)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From Sydney Genome Diagnostics, Children's Hospital Westmead, SCV001449189.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, SCV004030361.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (2)

Description

Clinical significance based on ACMG v2.0

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From GenomeConnect - Invitae Patient Insights Network, SCV004228911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	phenotyping only	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000926503	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD	flagged submission Reason: This record appears to be redundant with a more recent record from the same submitter. Notes: SCV000926503 appears to be redundant with SCV000926794.	Pathogenic (Apr 1, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000926503

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD

flagged submission

Reason: This record appears to be redundant with a more recent record from the same submitter.

Notes: SCV000926503 appears to be redundant with SCV000926794.

Pathogenic
(Apr 1, 2018)

unknown

research

PubMed (1)
[See all records that cite this PMID]

Last Updated: May 1, 2024

Relating variation to medicine