ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs773684291
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Total submissions: 8
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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

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