ClinVar Genomic variation as it relates to human health

Variant summary: MYH7 c.11C>T (p.Ser4Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250976 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.11C>T has been reported in the literature in settings of multigene panel /MYH7 specific testing among cohorts of individuals with Hypertrophic Cardiomyopathy reported as having no family history of HCM and/or hypertrophy (example, Garcio-Castro_2009, Coto_2012, Gomez_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Identified in at least one individual with HCM (Garcia-Castro et al., 2009; Coto et al., 2012; Gomez et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24510615, 25342278, 22765922, 19150014, 34542152)

This missense variant replaces serine with leucine at codon 4 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 25342278, 28356264). This variant has been identified in 7/250976 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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 4 of the MYH7 protein (p.Ser4Leu). This variant is present in population databases (rs758659692, gnomAD 0.009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 25342278). ClinVar contains an entry for this variant (Variation ID: 380650). 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 not expected to disrupt MYH7 protein function with a negative 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 p.S4L variant (also known as c.11C>T), located in coding exon 1 of the MYH7 gene, results from a C to T substitution at nucleotide position 11. The serine at codon 4 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in cardiomyopathy cohorts (Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10:; Ware JS et al. J Am Coll Cardiol, 2018 May;71:2293-2302). This alteration has also been reported in ostensibly healthy individuals (Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 Jun;113:6701-6; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

This missense variant replaces serine with leucine at codon 4 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least two individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 25342278, 28356264) and in one individual affected with alcoholic cardiomyopathy (PMID: 29773157). This variant has been identified in 7/250976 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.