ClinVar Miner

Submissions for variant NM_001232.4(CASQ2):c.925del (p.Asp309fs)

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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 RCV002371415 SCV002686495 likely pathogenic Cardiovascular phenotype 2021-06-30 criteria provided, single submitter clinical testing The c.925delG variant, located in coding exon 9 of the CASQ2 gene, results from a deletion of one nucleotide at nucleotide position 925, causing a translational frameshift with a predicted alternate stop codon (p.D309Tfs*26). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration occurs at the 3' terminus of theCASQ2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003526171 SCV004276622 pathogenic Catecholaminergic polymorphic ventricular tachycardia 1 2023-12-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp309Thrfs*26) in the CASQ2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 91 amino acid(s) of the CASQ2 protein. This variant is not present in population databases (gnomAD no frequency). 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: 1766367). 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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