ClinVar Miner

Submissions for variant NM_001232.4(CASQ2):c.1052A>G (p.Asp351Gly)

gnomAD frequency: 0.00001  dbSNP: rs200899037
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171633 SCV000050665 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Illumina Laboratory Services, Illumina RCV001093911 SCV000347672 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000768698 SCV000900068 uncertain significance Cardiomyopathy 2017-10-26 criteria provided, single submitter clinical testing
Invitae RCV002515247 SCV001201794 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 1 2022-04-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 351 of the CASQ2 protein (p.Asp351Gly). This variant is present in population databases (rs200899037, gnomAD 0.007%). This missense change has been observed in individual(s) with CASQ2-related conditions (PMID: 28074886, 28404607, 29032884). ClinVar contains an entry for this variant (Variation ID: 191441). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV003165354 SCV003866677 uncertain significance Cardiovascular phenotype 2023-01-06 criteria provided, single submitter clinical testing The p.D351G variant (also known as c.1052A>G), located in coding exon 11 of the CASQ2 gene, results from an A to G substitution at nucleotide position 1052. The aspartic acid at codon 351 is replaced by glycine, an amino acid with similar properties. This variant has been detected in two cases from a sudden infant death cohort and in a case with idiopathic ventricular fibrillation (Neubauer J et al. Eur J Hum Genet, 2017 Apr;25:404-409; Leinonen JT et al. Int J Cardiol, 2018 Jan;250:139-145). This variant has also been detected in exome sequencing cohorts; however, clinical details were limited (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10). Analyses by one group suggest this variant may not significantly impact certain aspects of protein folding and function (Wang Q et al. Sci Rep, 2020 Oct;10:18115). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.
Genome-Nilou Lab RCV001093911 SCV004050770 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2 2023-04-11 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000171633 SCV005186841 uncertain significance not provided criteria provided, single submitter not provided

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