Submissions for variant NM_001232.4(CASQ2):c.1017dup (p.Asp340Ter)

dbSNP: rs1553191909

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516551	SCV001400066	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2024-06-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp340*) in the CASQ2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the CASQ2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 32693635). ClinVar contains an entry for this variant (Variation ID: 190758). This variant disrupts a region of the CASQ2 protein in which other variant(s) (p.W361X) have been determined to be pathogenic (PMID: 23595086, 30729048). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002516551	SCV005887834	pathogenic	Catecholaminergic polymorphic ventricular tachycardia 1	2025-01-10	criteria provided, single submitter	clinical testing	Variant summary: CASQ2 c.1017dupT (p.Asp340X) results in a premature termination codon, predicted to cause a truncation of the encoded protein and not involved in nonsense-mediated mRNA decay. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250464 control chromosomes (gnomAD). c.1017dupT has been reported in the literature in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia (Prez-Riera_2017, Roston_2018, Ng_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32693635, 29048771, 28158428). ClinVar contains an entry for this variant (Variation ID: 190758). Based on the evidence outlined above, the variant was classified as pathogenic.