ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.5836T>C (p.Trp1946Arg)

dbSNP: rs137853017
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001851682 SCV002233858 pathogenic Spastic paraplegia 2023-10-06 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1946 of the SACS protein (p.Trp1946Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SACS-related conditions (PMID: 12873855, 23250129). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3662T>C, p.Trp1196Arg. ClinVar contains an entry for this variant (Variation ID: 5517). 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 SACS protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005852 SCV002766372 pathogenic Charlevoix-Saguenay spastic ataxia 2022-11-12 criteria provided, single submitter clinical testing Variant summary: SACS c.5836T>C (p.Trp1946Arg) 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 was absent in 250862 control chromosomes (gnomAD). c.5836T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g. El Euch-Fayache_2003, Thiffault_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Preventiongenetics, part of Exact Sciences RCV003415662 SCV004113816 likely pathogenic SACS-related condition 2022-09-22 criteria provided, single submitter clinical testing The SACS c.5836T>C variant is predicted to result in the amino acid substitution p.Trp1946Arg. This variant was reported in a family with Charlevoix-Saguenay spastic ataxia, segregating consistent with the cause of autosomal recessive disease in 3 affected and 3 unaffected siblings (El Euch-Fayache et al 2003. PubMed ID: 12873855). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
OMIM RCV000005852 SCV000026034 pathogenic Charlevoix-Saguenay spastic ataxia 2003-07-01 no assertion criteria provided literature only

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