ClinVar Genomic variation as it relates to human health

This alteration is classified as 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.

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.

Glu1833Val in exon 24 of DSP: This variant is not expected to have clinical sign ificance because it has been reported in multiple studies and in dbSNP at a freq uency of ~1% (Barahona-Dussault 2010, Gehmlich 2011, Garcia-Pavia 2011, Quarta 2 011, dbSNP rs78652302). In addition, this variant has been identified in 1.3% (9 2/7020) of European American chromosomes from a broad population by the NHLBI Ex ome Sequencing Project (http://evs.gs.washington.edu/EVS).

DSP: BP4, BS1, BS2

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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. This variant has been reported in one proband with ARVC who was homozygous for the variant and had no additional variants in the four desmosomal genes that were tested (PKP2, DSP, DSG2 and DSC2) (Brahona-Dussault et al 2010). Notably, the authors list the variant as a polymorphism with a minor allele frequency of 1.5%, though it is unclear where this allele frequency estimate is derived from. There is no segregation data on this variant. This is a non conservative amino acid change with a polar, negative Glutamic acid replaced with a nonpolar, neutral Valine. In silico analysis report conflicting results: SIFT predicts the amino acid change to be tolerated PolyPhen predicts the change to be possibly damaging. It is listed in dbSNP (rs 78652302). In a sample of 2276 individuals, 1.6% were heterozygous for the variant. No homozygotes were reported. Variants in DSP have not been linked to HCM, though they have been linked to both ARVC and DCM.