ClinVar Miner

Submissions for variant NM_021830.5(TWNK):c.1523A>G (p.Tyr508Cys)

gnomAD frequency: 0.00028  dbSNP: rs80356540
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199894 SCV000251226 pathogenic not provided 2016-06-06 criteria provided, single submitter clinical testing The Y508C variant in the C10orf2 gene has been reported previously in the homozygous state in multiple individuals with infantile onset spinocerebellar ataxia (IOSCA) (Nikali et al., 2005). Individuals who are compound heterozygous for the Y508C variant and another disease causing variant in C10orf2 may present with IOSCA or early onset cholestatic liver failure (Nikali et al., 2005; Goh et al., 2012). Heterozygous carriers of the Y508C variant are unaffected (Nikali et al., 2005). The Y508C variant is a founder mutation within the Finnish population (Nikali et al., 2005) yet rare outside this population, therefore the Y508C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Y508C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is well-conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret Y508C as a disease-causing variant.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000020865 SCV000680158 pathogenic Infantile onset spinocerebellar ataxia 2017-09-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000199894 SCV001961243 pathogenic not provided 2021-08-01 criteria provided, single submitter clinical testing
3billion RCV000020865 SCV002520993 likely pathogenic Infantile onset spinocerebellar ataxia 2022-05-22 criteria provided, single submitter clinical testing Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000004627, PMID:16135556). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.964>=0.6, 3CNET: 0.948>=0.75). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset (total allele frequency: dMAF: 0.00447, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity RCV000199894 SCV003816044 likely pathogenic not provided 2021-11-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000199894 SCV005835777 pathogenic not provided 2024-05-18 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 508 of the TWNK protein (p.Tyr508Cys). This variant is present in population databases (rs80356540, gnomAD 0.3%). This missense change has been observed in individuals with clinical features of autosomal recessive TWNK-related conditions (PMID: 16135556, 17921179, 21681116, 33486010). ClinVar contains an entry for this variant (Variation ID: 4627). 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 TWNK protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TWNK function (PMID: 16135556, 18775955, 20659899). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000020865 SCV000025066 pathogenic Infantile onset spinocerebellar ataxia 2005-10-15 no assertion criteria provided literature only
GeneReviews RCV000020865 SCV000041456 not provided Infantile onset spinocerebellar ataxia no assertion provided literature only

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