Submissions for variant NM_000257.4(MYH7):c.1750G>A (p.Gly584Ser)

gnomAD frequency: 0.00001  dbSNP: rs121913626

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000229519	SCV000059394	likely pathogenic	Hypertrophic cardiomyopathy	2019-04-05	criteria provided, single submitter	clinical testing	The p.Gly584Ser variant in MYH7 has been reported in >5 individuals with HCM (Erdmann 2003, Zou 2013, Kapplinger 2014, Homburger 2016, LMM unpublished), and was absent large population studies. Glycine (Gly) at position 584 is highly conserved in evolution and the change to Serine (Ser) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, another variant at this position, p.Gly584Arg, has been categorized as pathogenic, supporting that changes at this position are not tolerated. Of note, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Gly584Ser variant is likely pathogenic.The ACMG/AMP Criteria applied: PM1, PM2, PM5, PS4_Moderate, PP3.
Invitae	RCV000229519	SCV000284258	pathogenic	Hypertrophic cardiomyopathy	2023-11-24	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 584 of the MYH7 protein (p.Gly584Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 23283745, 24510615, 26187847, 26914223). ClinVar contains an entry for this variant (Variation ID: 42862). 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%. This variant disrupts the p.Gly584 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1552912, 8282798, 8335820, 24093860). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000242011	SCV000319779	likely pathogenic	Cardiovascular phenotype	2021-09-30	criteria provided, single submitter	clinical testing	The p.G584S variant (also known as c.1750G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1750. The glycine at codon 584 is replaced by serine, an amino acid with similar properties, This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in multiple patients with hypertrophic cardiomyopathy (HCM) (Erdmann J et al. Clin Genet. 2003;64(4):339-49; Zou Y et al. Mol Biol Rep. 2013;40(6):3969-76; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Murphy SL et al. J Cardiovasc Transl Res. 2016;9:153-61; Haskell GT et al. Circ Cardiovasc Genet. 2017;10:e001443). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709746	SCV000840023	likely pathogenic	Hypertrophic cardiomyopathy 1	2018-02-08	criteria provided, single submitter	clinical testing	The c.1750G>A (p.Gly584Ser) variant in the MYH7 gene has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (HCM) (PMID: 12974739, 23283745, 24510615, 27247418). This variant is absent from large databases of genetic variation in the general population. A different missense variant at the same position, (p.Gly584Arg), has also been reported in individuals with HCM (PMID: 24093860, 1552912, 8335820, 27532257, 27247418). The c.1750G>A (p.Gly584Ser) variant in the MYH7 gene is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035743	SCV000917844	pathogenic	Primary familial hypertrophic cardiomyopathy	2018-10-01	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1750G>A (p.Gly584Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247226 control chromosomes. c.1750G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy. A variant at the same codon, p.Gly584Arg, as well as variants in adjacent codons, have been associated with HCM, suggesting the codon and motif are critical for function. Together, these data indicate that the variant is very likely to be associated with disease. 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 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000788633	SCV000927812	pathogenic	not provided	2018-07-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149621	SCV003838484	pathogenic	Cardiomyopathy	2021-09-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788633	SCV004042578	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	MYH7: PM1, PM2, PM5, PS4:Moderate
Illumina Laboratory Services, Illumina	RCV000709746	SCV004101346	likely pathogenic	Hypertrophic cardiomyopathy 1	2023-08-10	criteria provided, single submitter	clinical testing	The MYH7 c.1750G>A (p.Gly584Ser) missense variant results in the substitution of glycine at position 584 with serine. This variant has been reported in a heterozygous state in seven individuals with hypertrophic cardiomyopathy (PMID: 12974739; 23283745; 24510615; 26914223; 31447099; 33673806; 28640247). Additionally, a different amino acid substitution at the same position (p.Gly584Arg) has been reported in individuals with hypertrophic cardiomyopathy (PMID: 1552912; 8282798; 8335820; 24093860), and has been classified as pathogenic by the ClinGen Cardiomyopathy Expert Panel (ClinVar: 14090). This variant is located in the myosin head domain, a known region critical for protein function (PMID: 29300372). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.1750G>A (p.Gly584Ser) variant is classified as likely pathogenic for hypertrophic cardiomyopathy.
All of Us Research Program, National Institutes of Health	RCV000229519	SCV004844790	likely pathogenic	Hypertrophic cardiomyopathy	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 584 of the myosin head/motor (S1) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 1552912, 12974739, 23283745, 24510615, 28611029, 28640247, 31308319, 33495597, 34310159). A different variant occurring at the same codon, p.Gly584Arg, is a well documented pathogenic mutation (Clinvar variation ID: 14090), indicating that glycine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.