ClinVar Genomic variation as it relates to human health

p.Arg1036Cys in exon 29 of MYBPC3: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 0.6% (58/9778) of African chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61729664).

This variant is associated with the following publications: (PMID: 24503780, 23861362, 22958901, 22763267, 27153395, 25524337, 28679633, 29121657, 25163546)

Variant summary: MYBPC3 c.3106C>T (p.Arg1036Cys) results in a non-conservative amino acid change located in the Immunoglobulin-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 245430 control chromosomes, predominantly at a frequency of 0.0056 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 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3106C>T has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. 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.