ClinVar Genomic variation as it relates to human health

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22198169, 24025405, 21618644, 22421959, 21454795, 23022705, 27538377, 21063088, 28818208, 28404607, 34426522, 25651173, 26671417, 18543230)

The Phe189Leu variant in CASQ2 has been reported in the heterozygous state in 1 individual with CPVT (Liu 2008). This variant is present at low frequency in var ious large populations, for example in 0.1% (9/8600) of European American chromo somes screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs146664754). Studies have shown that the Phe189Leu variant may i mpactthe protein (Eckey 2010). However, this in vitro assay may not accurately r epresent biological function. Computational analyses (biochemical amino acid pro perties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Phe189Le u variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the available information for this va riant is somewhat conflicting. Additional information is needed to fully assess its clinical significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

CASQ2: PM2:Supporting

The CASQ2 Phe189Leu variant has been previously reported in 2 CPVT families (Liu QQ, et al, 2008) and one sudden death case (Rajagopalan A & Pollanen MS, 2016). An in vitro functional study performed on Xenopus oocytes, has shown that the variant causes a reduction in hERG function and reduces flexbility of the CASQ2 protein, which suggests it may play a role in the aetiology of CPVT (Eckey K, et al., 2010). However, the use of an in vitro assay on amphibian oocytes may not reflect the actual biological function of the mutated protein in the mammalian heart. The CASQ2 Phe189Leu variant is present in the Exome Aggregation Consortium dataset (MAF= 0.0007, http://exac.broadinstitute.org/) and is particularly common in the European population; allele frequency=0.091, which is higher then expected for an inherited heart condition. We identified this variant in a case of sudden unexplained death in a young male. Genetic testing in this individual also identified two other variants (NEBL Gln682* & PKP2 Glu85Metfs*260), both of which are very rare. Furthermore, one study identified a substantial overrepresentation of CPVT-associated variants in an exome population database (ESP), the authors predict that these variants are not the monogenic cause of CPVT (Jabbari J, et al, 2013). In summary, based on the high allele frequency in the general population and lack of established functional data in mammalian models or other strong data supportive of a pathogenic role, we classify CASQ2 Phe189Leu as "likely benign".

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).