rs199750975

Description

The p.Ser113Asn variant in CASQ2 has not been reported in any other families wit h cardiomyopathy, but has been identified in 3/10514 African chromosomes and 2/6 6974 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs199750975). Computational prediction tools and cons ervation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser113Asn variant is unc ertain.

Variant summary: The CASQ2 c.338G>A (p.Ser113Asn) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Although the variant is located outsed of any know domain or repeat, the impact of this change on the protein have yet to be functionally assessed. This variant was found in 12/276958 control chromosomes at a frequency of 0.0000433, which does not exceed the estimated maximal expected allele frequency of a pathogenic CASQ2 variant (0.0044721). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)", until additional information becomes available.

p.Ser113Asn (AGC>AAC): c.338 G>A in exon 3 of the CASQ2 gene (NM_001232.3). The S113N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S113N variant was not observed with any significant frequency 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. Additionally, this substitution occurs at a position that is conserved among mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the S113N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, missense mutations in nearby residues have not been reported, 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).