Submissions for variant NM_001232.4(CASQ2):c.1185_1187del (p.Asp398del)

dbSNP: rs397516641

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170903	SCV000050813	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037134	SCV000060791	likely benign	not specified	2014-11-28	criteria provided, single submitter	clinical testing	p.Asp398del in exon 11 of CASQ2: This variant is an in-frame deletion of amino acid 398 at the very end of the last exon. It is not expected to have clinical s ignificance because it has been identified in 0.8% (557/67556) European chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs397516641). At this frequency this variant would explain more than half o f all cases of CPVT (an autosomal recessive condition with an estimated prevalen ce of 0.01%). This is highly unlikely given that multiple different variants hav e been associated with this disorder.
GeneDx	RCV000037134	SCV000223461	benign	not specified	2016-07-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics, part of Exact Sciences	RCV000037134	SCV000307074	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245930	SCV000319064	uncertain significance	Cardiovascular phenotype	2013-10-18	criteria provided, single submitter	clinical testing	Thec.1185_1187delvariant (also known as p.D395del) is located in codingexon 11 of the CASQ2 gene.This variant results from an in-frame 3 basepair deletion between nucleotide positions 1185 and 1187. This results in the deletion of an aspartic acid residue at codon 395. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at these positions. This amino acid position is not well conserved based on available sequence alignment. Since supporting evidence for this variant is limited at this time, the clinical significance of this variant remains unclear.​
Invitae	RCV002513463	SCV000559565	benign	Catecholaminergic polymorphic ventricular tachycardia 1	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000170903	SCV000697789	benign	not provided	2016-04-27	criteria provided, single submitter	clinical testing	Variant summary: The CASQ2 c.1185_1187delCGA leads to an in-frame deletion of one aspartic acid residue in a repetitive region of five aspartic acids in the penultimate exon. This variant was found in 665/121072 control chromosomes (including 5 homozygotes) from the broad and large populations of ExAC at a frequency of 0.0054926, which is significantly greater than the maximal expected frequency of a pathogenic CASQ2 allele (0.0044721) in this gene, suggesting this variant is benign. The variants allele frequency was highest in the European (Non-Finnish) sub-population with an allele frequency of 0.0083 (553/66608 chromosomes) including 5 homozygotes. The variant did not segregate with cardiological phenotype LVNC (Left Ventricular Non-Compaction) in two reported families (Hoedemaekers_2012) and it was also found to co-occur with a likely pathogenic variant (LMNA c.1146C>T) in one DCM patient (Pugh_2014), strongly supporting a benign classification for the variant of interest. It has also been classified as likely benign by one lab in ClinVar. Taken together, this variant has been classified as Benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625048	SCV000743622	benign	Catecholaminergic polymorphic ventricular tachycardia 2	2015-12-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769723	SCV000901144	benign	Cardiomyopathy	2017-11-17	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852588	SCV000995290	likely benign	Primary dilated cardiomyopathy	2019-05-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000170903	SCV001147387	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CASQ2: BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000625048	SCV002049205	benign	Catecholaminergic polymorphic ventricular tachycardia 2	2022-03-07	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000625048	SCV003924190	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 2	2021-03-30	criteria provided, single submitter	clinical testing	CASQ2 NM_001232.3 exon 11 p.Asp398del (c.1194_1196delTGA): This variant has been reported in the literature in at least 2 individuals with Left Ventricular Noncompaction (LVNC), but did not segregate with disease in affected family members. This variant was also identified in at least 1 individual with LVNC and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (Hoedemaekers 2010 PMID:20530761, Egan 2013 PMID:23476865). This variant is present in 0.7% (956/126210) of European alleles, including 8 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs751885773). This variant is present in ClinVar (Variation ID:190752). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame deletion of 1 amino acid at position 398 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Clinical Genetics, Academic Medical Center	RCV000037134	SCV001919606	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000170903	SCV001957448	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000170903	SCV001975813	likely benign	not provided		no assertion criteria provided	clinical testing