Submissions for variant NM_032977.4(CASP10):c.507C>G (p.Cys169Trp)

gnomAD frequency: 0.00004  dbSNP: rs774005416

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001137522	SCV000812729	uncertain significance	Autoimmune lymphoproliferative syndrome type 2A	2023-05-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 565644). This variant has not been reported in the literature in individuals affected with CASP10-related conditions. This variant is present in population databases (rs774005416, gnomAD 0.003%). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 169 of the CASP10 protein (p.Cys169Trp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt CASP10 protein function.
Illumina Laboratory Services, Illumina	RCV001137522	SCV001297467	uncertain significance	Autoimmune lymphoproliferative syndrome type 2A	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001137522	SCV004171504	uncertain significance	Autoimmune lymphoproliferative syndrome type 2A	2023-10-19	criteria provided, single submitter	clinical testing	The CASP10 c.507C>G (p.Cys169Trp) missense change has a maximum subpopulation frequency of 0.0035% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with autoimmune lymphoproliferative syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003980308	SCV004789527	uncertain significance	CASP10-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The CASP10 c.507C>G variant is predicted to result in the amino acid substitution p.Cys169Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.