Submissions for variant NM_001232.4(CASQ2):c.376G>C (p.Asp126His)

gnomAD frequency: 0.00004  dbSNP: rs727502908

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150227	SCV000197210	uncertain significance	not specified	2014-12-31	criteria provided, single submitter	clinical testing	The p.Asp126His variant in CASQ2 has not been reported in any other families wit h cardiomyopathy, but has been identified in 1/67530 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Asp126His variant is uncertain.
GeneDx	RCV000766686	SCV000223466	uncertain significance	not provided	2018-02-08	criteria provided, single submitter	clinical testing	The D126H variant of uncertain significance in the CASQ2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant has been identified in other unrelated individuals referred for arrhythmia genetic testing at GeneDx. The D126H variant is observed in 5/126,646 alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). The D126H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496815	SCV000588135	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 2	2016-12-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515273	SCV000611445	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1; Catecholaminergic polymorphic ventricular tachycardia 2	2017-05-23	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000150227	SCV000740439	uncertain significance	not specified	2016-07-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768704	SCV000900074	uncertain significance	Cardiomyopathy	2017-08-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345460	SCV002623218	uncertain significance	Cardiovascular phenotype	2024-11-17	criteria provided, single submitter	clinical testing	The p.D126H variant (also known as c.376G>C), located in coding exon 3 of the CASQ2 gene, results from a G to C substitution at nucleotide position 376. The aspartic acid at codon 126 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514883	SCV003506013	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 126 of the CASQ2 protein (p.Asp126His). This variant is present in population databases (rs727502908, gnomAD 0.004%). 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: 162818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CASQ2 protein function. 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.
Genome-Nilou Lab	RCV000496815	SCV004048954	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 2	2023-04-11	criteria provided, single submitter	clinical testing