ClinVar Genomic variation as it relates to human health

Thr1070Met in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it is not conserved across species, including mammals. Of note , >15 mammals have a methionine (Met) at this position. In addition, computation al prediction tools do not suggest a high likelihood of impact to the protein. I t has also been identified in 5/8274 of European American chromosomes and by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1496 17776).

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Variant summary: DSG2 c.3209C>T (p.Thr1070Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 277006 control chromosomes, predominantly at a frequency of 0.0087 within the Latino subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 348 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3209C>T has been reported in the literature among 870 participants not selected for arrhythmia, cardiomyopathy (Ng_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant predomiantly as likely benign/benign (4x) and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

This variant is associated with the following publications: (PMID: 30821013, 26230511)

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.