Submissions for variant NM_017777.4(MKS1):c.1208C>T (p.Ser403Leu)

gnomAD frequency: 0.00001  dbSNP: rs773684291

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201754	SCV000256442	pathogenic	Familial aplasia of the vermis	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV000479872	SCV000571461	likely pathogenic	not provided	2019-06-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26490104, 25363768, 26092869, 28714951)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853235	SCV002116610	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 403 of the MKS1 protein (p.Ser403Leu). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26490104, 28497568). ClinVar contains an entry for this variant (Variation ID: 217672). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230449	SCV003928473	uncertain significance	not specified	2023-04-24	criteria provided, single submitter	clinical testing	Variant summary: MKS1 c.1208C>T (p.Ser403Leu) 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 8e-06 in 249294 control chromosomes (gnomAD). c.1208C>T has been reported in the literature in at least one compound heterozygous individual affected with Joubert syndrome (Slaats_2016, Bachmann-Gagescu_2015, Summers_2017, Brooks_2018), in addition, the variant was also reported as de novo variant in heterozygous state in a patient affected with autism spectrum disorder (ASD) (e.g. Iossifov_2014, Koire_2021). These data do not allow clear conclusions about variant significance. One publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased cilium number and increased length in primary skin fibroblasts from an affected individual (Slaats_2016), however the variant protein was able to completely rescue ciliation defects in an MKS1-knockdown cell line (Slaats_2016). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as pathogenic (n=1), likely pathogenic (n=2), or VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000984285	SCV004194920	likely pathogenic	Bardet-Biedl syndrome 13	2024-01-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000984284	SCV001132434	uncertain significance	Meckel syndrome, type 1	2018-03-28	no assertion criteria provided	clinical testing
Counsyl	RCV000984285	SCV001132435	uncertain significance	Bardet-Biedl syndrome 13	2018-03-28	no assertion criteria provided	clinical testing
Counsyl	RCV000984286	SCV001132436	uncertain significance	Joubert syndrome 28	2018-03-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732785	SCV005362523	uncertain significance	MKS1-related disorder	2024-09-11	no assertion criteria provided	clinical testing	The MKS1 c.1208C>T variant is predicted to result in the amino acid substitution p.Ser403Leu. This variant was reported in an individual with Joubert syndrome (Slaats et al 2016. PubMed ID: 26490104) as well as in a cohort of autism spectrum disorder (Iossifov I et al 2014. PubMed ID: 25363768; Lim ET et al 2017. PubMed ID: 28714951). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.