Submissions for variant NM_000257.4(MYH7):c.3301G>A (p.Gly1101Ser)

gnomAD frequency: 0.00002  dbSNP: rs367546859

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766444	SCV000208536	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing	Reported in association with HCM and idiopathic ventricular fibrillation; however, detailed clinical information and segregation data were not provided (Curila et al., 2012; Visser et al., 2017; Magri et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28087426, 25637381, 23299917, 32481709, 22455086)
Ambry Genetics	RCV000250091	SCV000318275	uncertain significance	Cardiovascular phenotype	2021-04-07	criteria provided, single submitter	clinical testing	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, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455124	SCV000539834	uncertain significance	not specified	2016-04-25	criteria provided, single submitter	clinical testing	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
Invitae	RCV000544518	SCV000623694	uncertain significance	Hypertrophic cardiomyopathy	2024-01-29	criteria provided, single submitter	clinical testing	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). ClinVar contains an entry for this variant (Variation ID: 161325). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000148706	SCV000987504	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001175841	SCV001339612	uncertain significance	Cardiomyopathy	2022-12-02	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455124	SCV001774504	uncertain significance	not specified	2021-07-27	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000766444	SCV003817680	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148706	SCV000190436	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research