ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 31127036)

PM2, PVS1

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.

This sequence change creates a premature translational stop signal (p.Asn63Metfs*7) in the MYL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MYL2 cause disease. This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with congenital fiber type disproportion and fatal infantile cardiomyopathy (PMID: 31127036). ClinVar contains an entry for this variant (Variation ID: 928166). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

This variant deletes 1 nucleotide in exon 4 of the MYL2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in homozygosity in an individual affected with congenital fiber type disproportion and fatal infantile cardiomyopathy (PMID: 31127036). This individual also carried a heterozygous nonsense mutation in the nebulin (NEB) gene. This variant has been identified in 1/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function MYL2 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The c.188delA variant, located in coding exon 4 of the MYL2 gene, results from a deletion of one nucleotide at nucleotide position 188, causing a translational frameshift with a predicted alternate stop codon (p.N63Mfs*7). This alteration has been reported as homozygous in an individual with concerns for myofibrillar myopathy and cardiomyopathy (Marttila M et al. Cold Spring Harb Mol Case Stud, 2019 08;5:[ePub ahead of print]). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function alterations in MYL2 have been associated with autosomal recessive MYL2-related myofibrillar myopathy with cardiomyopathy, haploinsufficiency for MYL2 has not been clearly established as a mechanism of disease for autosomal dominant MYL2-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.