Submissions for variant NM_001232.4(CASQ2):c.1188TGA[2] (p.Asp398del)

dbSNP: rs72554070

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000223769	SCV000223462	likely benign	not specified	2016-11-14	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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223769	SCV000280061	uncertain significance	not specified	2011-04-14	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we initially classified it as a VUS. However, we now believe it is a VUS that is probably benign based on new data from ExAC (see below). p.Asp398del has not been reported as a disease-causing variant, and it is not present in HGMD as of August 2014. It has previously been reported in two families with left ventricular non-compaction (LVNC) by Hoegemaekers et al. (2010); however, the variant did not co-segregate with disease in either family. This variant has also been detected in a 5-year-old girl with bradycardia, exercise-induced arrhythmias including bidirectional VT (consistent with CPVT) and a heavily trabeculated LV—but the patient also reportedly had an R169Q variant in the RYR2 gene and a K4455R variant in the TTN gene (Egan et al. 2013). This variant involves an in-frame deletion of an aspartic acid that is part of a string of 5 negatively-charged aspartic acid residues at the C-terminal end of the protein. These aspartic acid residues vary somewhat across vertebrate species. Deletion of one of these C-terminal aspartic acids has not been reported in ~6000 individuals from publicly available population datasets. It is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1800 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no deletion of this amino acid listed in 1000 Genomes (as of November 3, 2014). An updated assessment on 10/5/2015 found that variation at this codon has been seen frequently in the ExAC dataset. It is most common in Caucasians: 598 Caucasians in ExAC have this variant, and 5 of them are homozygotes. It is also found in 28 African, 16 Latino, 16 South Asian, 1 East Asian, and 1 "other" for a total allele frequency of 0.5% overall and 0.8% in Caucasians. ExAC contains ~60,000 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases.