ClinVar Miner

Submissions for variant NM_001232.4(CASQ2):c.673A>G (p.Ile225Val)

gnomAD frequency: 0.00002  dbSNP: rs774546117
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001098684 SCV001255067 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002556008 SCV002210848 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2025-01-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 225 of the CASQ2 protein (p.Ile225Val). This variant is present in population databases (rs774546117, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 875120). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CASQ2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002365798 SCV002666954 uncertain significance Cardiovascular phenotype 2023-12-30 criteria provided, single submitter clinical testing The p.I225V variant (also known as c.673A>G), located in coding exon 6 of the CASQ2 gene, results from an A to G substitution at nucleotide position 673. The isoleucine at codon 225 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV001098684 SCV004048921 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2 2023-04-11 criteria provided, single submitter clinical testing

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