VCV000550801.16 - ClinVar

NM_031885.5(BBS2):c.565C>T (p.Arg189Ter)

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.

(5)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_031885.5(BBS2):c.565C>T (p.Arg189Ter)

Variation ID: 550801 Accession: VCV000550801.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56510004 (GRCh38) [ NCBI UCSC ] 16: 56543916 (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	Aug 5, 2018	Jun 17, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_031885.5:c.565C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_114091.4:p.Arg189Ter	nonsense
NM_001377456.1:c.565C>T	NP_001364385.1:p.Arg189Ter	nonsense
NR_165293.1:n.727C>T		non-coding transcript variant
NR_165294.1:n.727C>T		non-coding transcript variant
NR_165295.1:n.727C>T		non-coding transcript variant
NR_165296.1:n.727C>T		non-coding transcript variant
NR_165297.1:n.727C>T		non-coding transcript variant
NC_000016.10:g.56510004G>A
NC_000016.9:g.56543916G>A
NG_009312.2:g.15021C>T

... more HGVS ... less HGVS

Protein change

R189*

Other names

Canonical SPDI

NC_000016.10:56510003:G:A

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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

dbSNP: rs1273181642 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.
BBS2		-	-	GRCh38 GRCh37	1142	1180

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 2	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 20, 2024	RCV000665648.5
Bardet-Biedl syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000796443.10

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 (Feb 21, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Bardet-Biedl syndrome 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000789802.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 16877420
Pathogenic (Jun 22, 2020)	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: SCV001372323.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020	Publications: PubMed (3) PubMed: 23432027‚ 28800606‚ 16877420 Comment: Variant summary: BBS2 c.565C>T (p.Arg189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: BBS2 c.565C>T (p.Arg189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251318 control chromosomes (gnomAD). c.565C>T has been reported in the literature in multiple homozygous individuals affected with Bardet-Biedl Syndrome (e.g. Castro-Sanchez_2017, Mhamdi_2014, Smaoui_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 01, 2023)	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: SCV000935957.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (7) PubMed: 11285252‚ 20177705‚ 24608809‚ 26518167‚ 16877420‚ 23432027‚ 28800606 Comment: This sequence change creates a premature translational stop signal (p.Arg189) in the BBS2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg189) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16877420, 23432027, 28800606). ClinVar contains an entry for this variant (Variation ID: 550801). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bardet-Biedl syndrome 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004214035.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 21, 2021)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089300.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Variant summary: BBS2 c.565C>T (p.Arg189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251318 control chromosomes (gnomAD). c.565C>T has been reported in the literature in multiple homozygous individuals affected with Bardet-Biedl Syndrome (e.g. Castro-Sanchez_2017, Mhamdi_2014, Smaoui_2006). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg189*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (no rsID available, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16877420, 23432027, 28800606). ClinVar contains an entry for this variant (Variation ID: 550801). For these reasons, this variant has been classified as Pathogenic.

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
Whole exome sequencing as a diagnostic tool for patients with ciliopathy-like phenotypes.	Castro-Sánchez S	PloS one	2017	PMID: 28800606
Targeted multi-gene panel testing for the diagnosis of Bardet Biedl syndrome: Identification of nine novel mutations across BBS1, BBS2, BBS4, BBS7, BBS9, BBS10 genes.	Ece Solmaz A	European journal of medical genetics	2015	PMID: 26518167
Comprehensive molecular diagnosis of Bardet-Biedl syndrome by high-throughput targeted exome sequencing.	Xing DJ	PloS one	2014	PMID: 24608809
Clinical and genetic characterization of Bardet-Biedl syndrome in Tunisia: defining a strategy for molecular diagnosis.	M'hamdi O	Clinical genetics	2014	PMID: 23432027
Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.	Muller J	Human genetics	2010	PMID: 20177705
Screening of the eight BBS genes in Tunisian families: no evidence of triallelism.	Smaoui N	Investigative ophthalmology & visual science	2006	PMID: 16877420
Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2).	Nishimura DY	Human molecular genetics	2001	PMID: 11285252

Text-mined citations for rs1273181642 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_031885.5(BBS2):c.565C>T (p.Arg189Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1273181642 ...