ClinVar Miner

Submissions for variant NM_001232.4(CASQ2):c.164A>G (p.Tyr55Cys)

gnomAD frequency: 0.00002  dbSNP: rs1436844070
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, University of Leuven RCV000497364 SCV000579515 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2 2017-02-09 criteria provided, single submitter clinical testing ACMG score likely pathogenic
Ambry Genetics RCV000618128 SCV000738105 likely pathogenic Cardiovascular phenotype 2021-05-13 criteria provided, single submitter clinical testing The p.Y55C variant (also known as c.164A>G), located in coding exon 1 of the CASQ2 gene, results from an A to G substitution at nucleotide position 164. The tyrosine at codon 55 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in conjunction with other alterations in CASQ2 in compound heterozygous catecholaminergic polymorphic ventricular tachycardia (CPVT) cases; however, in some cases, cis or trans phase information was not provided (de la Fuente S et al. Pacing Clin Electrophysiol. 2008;31:916-9; Roux-Buisson N et al. Hum. Mutat. 2011 Sep;32(9):995-9; Robyns T et al. Eur J Hum Genet, 2017 12;25:1313-1323; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV002526063 SCV002276310 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2023-11-11 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 55 of the CASQ2 protein (p.Tyr55Cys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (CPVT) (PMID: 18684293, 21618644). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 427946). 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 CASQ2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CASQ2 function (PMID: 32693635). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000497364 SCV004048983 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2 2023-04-11 criteria provided, single submitter clinical testing

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