Submissions for variant NM_017777.4(MKS1):c.1476T>G (p.Cys492Trp)

gnomAD frequency: 0.00003  dbSNP: rs137853105

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626942	SCV000747645	pathogenic	Polydactyly; Nystagmus; Hypotonia	2017-01-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000665962	SCV000790181	uncertain significance	Bardet-Biedl syndrome 13; Meckel syndrome, type 1; Joubert syndrome 28	2017-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239533	SCV001412411	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 492 of the MKS1 protein (p.Cys492Trp). This variant is present in population databases (rs137853105, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome or Joubert syndrome (PMID: 18327255, 28497568, 34008892; 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: 1393). 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 MKS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MKS1 function (PMID: 18327255). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001578018	SCV001805533	uncertain significance	not provided	2021-01-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18327255, 28497568)
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729331	SCV001976732	likely pathogenic	Joubert syndrome 28	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PM3, PP3, PP5
PreventionGenetics, part of Exact Sciences	RCV004532272	SCV004115151	uncertain significance	MKS1-related disorder	2023-06-07	criteria provided, single submitter	clinical testing	The MKS1 c.1476T>G variant is predicted to result in the amino acid substitution p.Cys492Trp. This variant has been reported in two individuals with BBS; these two individuals harbored a second variant of uncertain significance in MKS1 (Leitch et al. 2008. PubMed ID: 18327255; Summers et al. 2017. PubMed ID: 28497568). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56283840-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000001458	SCV004194924	likely pathogenic	Bardet-Biedl syndrome 13	2024-03-30	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566669	SCV005051862	likely pathogenic	Meckel syndrome, type 1	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000001458	SCV000021613	pathogenic	Bardet-Biedl syndrome 13	2008-04-01	no assertion criteria provided	literature only