Submissions for variant NM_024685.4(BBS10):c.1677C>A (p.Tyr559Ter)

dbSNP: rs375413604

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818478	SCV000959093	pathogenic	Bardet-Biedl syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr559*) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs375413604, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 20472660, 27788217, 28808579). ClinVar contains an entry for this variant (Variation ID: 417949). This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075280	SCV001240896	pathogenic	Retinal dystrophy	2017-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000818478	SCV001338546	pathogenic	Bardet-Biedl syndrome	2020-04-24	criteria provided, single submitter	clinical testing	Variant summary: BBS10 c.1677C>A (p.Tyr559X) 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 4e-05 in 251128 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (4e-05 vs 0.0014). c.1677C>A has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Billingsley_2010, Feuillan_2011, Knopp_2015, Ohto_2017, Wang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001528233	SCV001823891	pathogenic	not provided	2019-06-04	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 165 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000916670.1; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30029678, 28808579, 27788217, 26003401, 21642631, 20472660, 25366773)
Revvity Omics, Revvity	RCV000477827	SCV002017349	pathogenic	Bardet-Biedl syndrome 10	2021-10-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000477827	SCV002811652	pathogenic	Bardet-Biedl syndrome 10	2022-02-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000477827	SCV004217407	pathogenic	Bardet-Biedl syndrome 10	2024-03-26	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477827	SCV000536909	likely pathogenic	Bardet-Biedl syndrome 10	2016-08-23	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528233	SCV001739619	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528233	SCV001951022	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000477827	SCV002091750	pathogenic	Bardet-Biedl syndrome 10	2020-08-18	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003960121	SCV004769135	pathogenic	BBS10-related disorder	2024-09-16	no assertion criteria provided	clinical testing	The BBS10 c.1677C>A variant is predicted to result in premature protein termination (p.Tyr559*). This variant has been reported in patients with Bardet-Biedl syndrome and retinal disorders (Billingsley et al. 2010. PubMed ID: 20472660; Wang et al. 2016. PubMed ID: 27788217; Ohto et al. 2017. PubMed ID: 28808579). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS10 are expected to be pathogenic. This variant is interpreted as pathogenic.