ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

This variant is associated with the following publications: (PMID: 32833721, 28798025, 18761664, 23299917, 25637381, 27532257, 25569433, 27247418, 12707239)

This missense variant replaces valine with methionine at codon 39 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 18761664, 27247418, 27532257), as well as in an individual affected with Laing distal myopathy (PMID: 32833721). However, some of those individuals also carried a pathogenic variant in the same gene, which suggests that this variant was probably not the primary cause of disease in these individuals. This variant has also been reported in an individual who was not affected with hypertrophic cardiomyopathy (PMID: 30052928). This variant has been identified in 13/282858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 39 of the MYH7 protein (p.Val39Met). This variant is present in population databases (rs376160714, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, Laing distal myopathy, and/or left ventricular noncompaction (PMID: 12707239, 27247418, 27532257, 28798025, 32833721). ClinVar contains an entry for this variant (Variation ID: 42827). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.

The c.115G>A (p.V39M) alteration is located in exon 3 (coding exon 1) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 115, causing the valine (V) at amino acid position 39 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.