ClinVar Genomic variation as it relates to human health

Variant summary: MYL2 c.188delA (p.Asn63MetfsX7) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in MYL2 as causative of dominantly inherited disease (example, PMID:32453731). The variant allele was found at a frequency of 4e-06 in 251482 control chromosomes (gnomAD). c.188delA has been reported in the literature in the homozygous state in an individual affected with congenital fiber-type disproportion and cardiomyopathy (Martilla_2019), and this individual also had a heterozygous truncating variant in NEB. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31127036, 35629155). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Variant summary: UMPS c.188delA (p.Asn63MetfsX47) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251426 control chromosomes. To our knowledge, no occurrence of c.188delA in individuals affected with Orotic Aciduria and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.