VCV000496478.21 - ClinVar

NM_031885.5(BBS2):c.2107C>T (p.Arg703Ter)

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.

(9)

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_031885.5(BBS2):c.2107C>T (p.Arg703Ter)

Variation ID: 496478 Accession: VCV000496478.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56484820 (GRCh38) [ NCBI UCSC ] 16: 56518732 (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	Mar 17, 2018	Oct 8, 2024	Mar 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_031885.5:c.2107C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_114091.4:p.Arg703Ter	nonsense
NM_001377456.1:c.2107C>T	NP_001364385.1:p.Arg703Ter	nonsense
NR_165293.1:n.2397C>T		non-coding transcript variant
NR_165294.1:n.2394C>T		non-coding transcript variant
NR_165295.1:n.2225C>T		non-coding transcript variant
NR_165296.1:n.2097C>T		non-coding transcript variant
NR_165297.1:n.2097C>T		non-coding transcript variant
NC_000016.10:g.56484820G>A
NC_000016.9:g.56518732G>A
NG_009312.2:g.40205C>T

... more HGVS ... less HGVS

Protein change

R703*

Other names

Canonical SPDI

NC_000016.10:56484819: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.

0.00020 (A)

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

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA8065521 dbSNP: rs567573386 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	Likely pathogenic (3)	criteria provided, single submitter	Mar 20, 2024	RCV000667111.4
Bardet-Biedl syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV000590291.10
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 24, 2017	RCV000622316.2
Retinitis pigmentosa 74	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV001376258.2
BBS2-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jan 8, 2024	RCV004530646.2

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.
Likely pathogenic (Jun 22, 2017)	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: SCV000699656.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (3) PubMed: 25988237‚ 25999675‚ 21344540
Likely pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 74 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573337.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Comment: The BBS2 c.2107C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The BBS2 c.2107C>T 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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. (less)
Likely pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 74 Affected status: yes Allele origin: germline	3billion Accession: SCV002521102.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (1) PubMed: 21344540 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000496478 / PMID: 21344540). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Visual impairment (present)
Likely pathogenic (Jan 24, 2017)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742127.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Number of individuals with the variant: 1 Clinical Features: Overgrowth (present) , Obesity (present) , Global developmental delay (present) , Autistic disorder of childhood onset (present) , Cyst of the ductus choledochus (present) , … (more) Overgrowth (present) , Obesity (present) , Global developmental delay (present) , Autistic disorder of childhood onset (present) , Cyst of the ductus choledochus (present) , Acanthosis nigricans (present) , Deeply set eye (present) , Small hand (present) , Short foot (present) , Short toe (present) , Joint laxity (present) , Muscular hypotonia (present) , Short finger (present) (less) Sex: male Ethnicity/Population group: Asian
Pathogenic (Jan 11, 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: SCV000958736.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 21344540‚ 25999675 Comment: This sequence change creates a premature translational stop signal (p.Arg703) in the BBS2 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg703) in the BBS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the BBS2 protein. This variant is present in population databases (rs567573386, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with BBS2-related disease (PMID: 21344540, 25999675; Invitae). ClinVar contains an entry for this variant (Variation ID: 496478). For these reasons, this variant has been classified as Pathogenic. (less)
Likely 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: SCV004213980.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (May 15, 2017)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000791510.2 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 25999675‚ 21344540‚ 27659767
Likely pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Bardet-Biedl syndrome type 2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457430.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely pathogenic (Jan 08, 2024)	no assertion criteria provided Method: clinical testing	BBS2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004744331.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The BBS2 c.2107C>T variant is predicted to result in premature protein termination (p.Arg703). This variant has been reported in the homozygous state or with a … (more) The BBS2 c.2107C>T variant is predicted to result in premature protein termination (p.Arg703). This variant has been reported in the homozygous state or with a second BBS2 variant in individuals with Bardet-Biedl syndrome (Deveault et al. 2011. PubMed ID: 21344540; Supplemental Table 1, Forsythe et al. 2016. PubMed ID: 27659767; Table S3, Fu et al. 2022. PubMed ID: 36307859) and reported in the homozygous state in an individual with retinitis pigmentosa (Xu et al. 2015. PubMed ID: 25999675). In addition, at PreventionGenetics, this variant has been seen in the homozygous or compound heterozygous states in individuals with features of Bardet-Biedl syndrome (Internal Data). This variant is reported in 0.027% of alleles in individuals of East Asian descent in a large population database. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as likely pathogenic. (less)

Comment:

The BBS2 c.2107C>T 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: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000496478 / PMID: 21344540). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Arg703*) in the BBS2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the BBS2 protein. This variant is present in population databases (rs567573386, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with BBS2-related disease (PMID: 21344540, 25999675; Invitae). ClinVar contains an entry for this variant (Variation ID: 496478). For these reasons, this variant has been classified as Pathogenic.

Comment:

The BBS2 c.2107C>T variant is predicted to result in premature protein termination (p.Arg703*). This variant has been reported in the homozygous state or with a second BBS2 variant in individuals with Bardet-Biedl syndrome (Deveault et al. 2011. PubMed ID: 21344540; Supplemental Table 1, Forsythe et al. 2016. PubMed ID: 27659767; Table S3, Fu et al. 2022. PubMed ID: 36307859) and reported in the homozygous state in an individual with retinitis pigmentosa (Xu et al. 2015. PubMed ID: 25999675). In addition, at PreventionGenetics, this variant has been seen in the homozygous or compound heterozygous states in individuals with features of Bardet-Biedl syndrome (Internal Data). This variant is reported in 0.027% of alleles in individuals of East Asian descent in a large population database. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as likely 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
Risk Factors for Severe Renal Disease in Bardet-Biedl Syndrome.	Forsythe E	Journal of the American Society of Nephrology : JASN	2017	PMID: 27659767
Exploration of the cognitive, adaptive and behavioral functioning of patients affected with Bardet-Biedl syndrome.	Kerr EN	Clinical genetics	2016	PMID: 25988237
Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing.	Xu Y	Molecular vision	2015	PMID: 25999675
BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition.	Deveault C	Human mutation	2011	PMID: 21344540

Text-mined citations for rs567573386 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_031885.5(BBS2):c.2107C>T (p.Arg703Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs567573386 ...