ClinVar Miner

Submissions for variant NM_001232.4(CASQ2):c.1028G>A (p.Trp343Ter)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV003301708 SCV004001938 pathogenic Cardiovascular phenotype 2023-05-09 criteria provided, single submitter clinical testing The p.W343* pathogenic mutation (also known as c.1028G>A), located in coding exon 11 of the CASQ2 gene, results from a G to A substitution at nucleotide position 1028. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. This alteration occurs at the 3' terminus of theCASQ2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 57 amino acids (14.3%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV003777184 SCV004683140 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2024-03-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp343*) in the CASQ2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acid(s) of the CASQ2 protein. This variant is present in population databases (rs529562535, gnomAD 0.02%). 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: 2565185). This variant disrupts a region of the CASQ2 protein in which other variant(s) (p.Leu366Pro) have been determined to be pathogenic (PMID: 32693635). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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