Submissions for variant NM_024685.4(BBS10):c.1838A>G (p.Tyr613Cys)

gnomAD frequency: 0.00002  dbSNP: rs575957641

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175947	SCV000227523	uncertain significance	not provided	2014-06-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000671818	SCV000796840	uncertain significance	Bardet-Biedl syndrome 10	2018-01-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000175947	SCV002504244	likely pathogenic	not provided	2019-03-05	criteria provided, single submitter	clinical testing	Functional studies demonstrate a damaging effect (Zaghloul et al., 2010); This variant is associated with the following publications: (PMID: 20498079, 16582908)
Invitae	RCV002516694	SCV003287094	pathogenic	Bardet-Biedl syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 613 of the BBS10 protein (p.Tyr613Cys). This variant is present in population databases (rs575957641, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 16582908; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195379). 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 BBS10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS10 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002516694	SCV004021219	likely pathogenic	Bardet-Biedl syndrome	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: BBS10 c.1838A>G (p.Tyr613Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247514 control chromosomes (gnomAD). c.1838A>G has been reported in the literature in compound heterozygous individual(s) affected with Bardet-Biedl Syndrome who carried a pathogenic variant in trans (Stoetzel_2006). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that this variant results in a null allele in a zebrafish model (Zaghloul_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20498079, 16582908). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant a pathogenic, likely pathogenic, or VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000175947	SCV001930360	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000175947	SCV001957314	pathogenic	not provided		no assertion criteria provided	clinical testing