Submissions for variant NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser)

gnomAD frequency: 0.00001  dbSNP: rs397516179

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000475413	SCV000564443	likely pathogenic	Hypertrophic cardiomyopathy	2021-12-09	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.3169G>A (p.Gly1057Ser) variant has been identified in >20 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease and 2 individuals with DCM (PS4; Van Driest 2004 PMID 15358028; Kapplinger 2014 PMID:24510615, Walsh 2017 PMID:27532257; Hazebroek 2018 PMID:24510615; Ho 2018 PMID: 30297972; van Lint 2019 PMID: 30847666; Robyns 2020 PMID: 31513939; Verdonschot 2020 PMID: 32880476; Ambry pers. comm; ARUP pers. comm; GeneDx pers. comm.; Invitae pers. comm; LMM pers. comm.). Additionally, this variant has also been reported in 1 individual with RCM and AFib, 4 individuals with unspecified heart disease or cardiomyopathy and 1 individual with LVH, CHD and trisomy 21 (Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035843	SCV000059494	uncertain significance	not specified	2017-08-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1057Se r variant in MYH7 has been reported in 9 individuals with HCM (Van Driest 2004, Kapplinger 2014, LMM data), but was also present in one of these individual's un affected, elderly parent. This variant has also been identified in 1/66738 Europ ean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs397516179). Glycine (Gly) at position 1057 is highly conserve d in mammals and across evolutionarily distant species and the change to serine (Ser) was predicted to be pathogenic using a computational tool clinically valid ated by our laboratory. This tool's pathogenic prediction is estimated to be cor rect 94% of the time (Jordan 2011). In summary, while there is some suspicion fo r a pathogenic role, the clinical significance of the p.Glu1057Ser variant is un certain.
GeneDx	RCV000766440	SCV000208528	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15358028, 27532257, 24510615, 21310275, 29300372, 29540472, 31513939, 30847666, 16199542, 32894683, 32880476, 30297972, 34542152, 29255176, 31568572)
Ambry Genetics	RCV000244617	SCV000320054	likely pathogenic	Cardiovascular phenotype	2023-06-05	criteria provided, single submitter	clinical testing	The p.G1057S variant (also known as c.3169G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3169. The glycine at codon 1057 is replaced by serine, an amino acid with similar properties. This variant has been identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am Coll Cardiol 2004 Aug; 44(3):602-10; Kapplinger JD et al. J Cardiovasc Transl Res 2014 Apr; 7(3):347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Hazebroek MR et al. Circ Heart Fail. 2018;11:e004682; Ambry internal data). In one family with HCM, this variant was seen in two affected relatives and one unaffected relative (Robyns T et al. Eur J Hum Genet. 2017;25(12):1313-1323). This variant is considered to be rare based on population 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.
Invitae	RCV000475413	SCV000546183	pathogenic	Hypertrophic cardiomyopathy	2023-12-04	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 1057 of the MYH7 protein (p.Gly1057Ser). This variant is present in population databases (rs397516179, gnomAD 0.002%). This missense change has been observed in individuals with MYH7-related conditions (PMID: 15358028, 27532257, 29255176, 30297972, 30847666, 31513939; Invitae). ClinVar contains an entry for this variant (Variation ID: 42950). 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.Gly1057 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 29398688), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, University of Leuven	RCV000475413	SCV000579537	uncertain significance	Hypertrophic cardiomyopathy	2017-02-09	criteria provided, single submitter	clinical testing	ACMG score unknown significance
Color Diagnostics, LLC DBA Color Health	RCV001190251	SCV001357702	likely pathogenic	Cardiomyopathy	2023-11-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1057 in the neck and hinge domain (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over ten unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 27476098, 27532257, 30297972, 30847666, 31568572, 33029862, 33495596; DOI:10.1038/s41431-019-0404-7) or suspected to be affected with hypertrophic cardiomyopathy (PMID: 24510615). This variant has been identified in 2/251486 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000766440	SCV002502947	uncertain significance	not provided	2021-11-05	criteria provided, single submitter	clinical testing