Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report, no segs; ExAC: 1/8654 East Asian chromosomes

Variant summary: MYH7 c.3301G>A (p.Gly1101Ser) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251630 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in MYH7 causing Cardiomyopathy (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.3301G>A has been reported in the literature in individuals affected with Hypertrophic cardiomyopathy and Idiopathic ventricular fibrillation (Curila_2012, Visser_2017, Magri_2020). These reports 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. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The p.G1101S variant (also known as c.3301G>A), located in coding exon 24 of the MYH7 gene, results from a G to A substitution at nucleotide position 3301. The glycine at codon 1101 is replaced by serine, an amino acid with similar properties. This variant has been reported in one individual with hypertrophic cardiomyopathy (HCM) and in an individual with idiopathic ventricular fibrillation who also had additional cardiac variant(s) (Curila K et al. Acta Cardiol, 2012 Feb;67:23-9; Visser M et al. Heart Rhythm, 2017 07;14:1035-1040). This variant was detected in a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been seen in exome cohorts, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is not well 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.

Reported in association with HCM, DCM, ARVC, and idiopathic ventricular fibrillation; however, detailed clinical information and segregation data were not provided (PMID: 22455086, 28087426, 30847666, 32481709, 35653365, 37466024); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28087426, 25637381, 23299917, 32481709, 35629155, 30847666, 37466024, 35653365, 22455086)

This missense variant replaces glycine with serine at codon 1101 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 22455086). This variant has been identified in 15/251430 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 missense variant replaces glycine with serine at codon 1101 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 22455086). This variant has been identified in 15/251430 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1101 of the MYH7 protein (p.Gly1101Ser). This variant is present in population databases (rs367546859, gnomAD 0.009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or idiopathic ventricular fibrillation (PMID: 22455086, 28087426, 32481709, 37466024). ClinVar contains an entry for this variant (Variation ID: 161325). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.