ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 21636032, 21859740)

Variant summary: DSG2 c.3295A>G (p.Thr1099Ala) 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 0.00039 in 281622 control chromosomes, predominantly at a frequency of 0.0041 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 410 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSG2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3295A>G has been reported in the literature in one individual affected with DCM (Garcia-Pavia_2011). The data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.

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.

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.

Thr1099Ala in exon 15 of DSG2: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (15/3328) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs79068489). Thr1099Ala in exon 15 of DSG2 (r s79068489; allele frequency = 0.5%, 15/3328) **

DSG2 NM_001943.4 exon 15 p.Thr1099Ala (c.3295A>G): This variant has not been reported in the literature and is present in 0.4% (98/24186) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-29126644-A-G). This variant is also present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:44314). This variant amino acid Alanine (Ala) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.

DSG2: BP4

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).