Submissions for variant NM_001232.4(CASQ2):c.118A>G (p.Lys40Glu)

dbSNP: rs786205797

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170912	SCV000223470	uncertain significance	not provided	2015-02-05	criteria provided, single submitter	clinical testing	p.Lys40Glu (AAG>GAG): c.118 A>G in exon 1 of the CASQ2 gene (NM_001232.3) The K40E variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The K40E variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K40E 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. Additionally, this substitution occurs at a position that is conserved among mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, only one missense mutation in a nearby residue (R33Q) has been reported in association with CPVT, indicating this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in ARRHYTHMIA panel(s).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000496259	SCV000588133	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 2	2016-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336401	SCV002642683	uncertain significance	Cardiovascular phenotype	2024-11-17	criteria provided, single submitter	clinical testing	The p.K40E variant (also known as c.118A>G), located in coding exon 1 of the CASQ2 gene, results from an A to G substitution at nucleotide position 118. The lysine at codon 40 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. 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	RCV002515232	SCV002950678	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2024-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 40 of the CASQ2 protein (p.Lys40Glu). 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: 190757). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000496259	SCV004048986	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 2	2023-04-11	criteria provided, single submitter	clinical testing