ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs397516179
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
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 RCV000475413 SCV000059494 likely pathogenic Hypertrophic cardiomyopathy 2022-02-24 criteria provided, single submitter clinical testing The p.Gly1057Ser variant in MYH7 has been identified in >20 individuals with hypertrophic cardiomyopathy (HCM), including 1 individual with an additional variant in another gene that may contribute to their disease and in 2 individuals with DCM (Van Driest 2004 PMID: 15358028; Kapplinger 2014 PMID: 24510615, Walsh 2017 PMID: 27532257; Hazebroek 2018 PMID: 29540472; 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.). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In addition, this variant was classified as likely pathogenic on Feb 25, 2019 by the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar Variation ID: 42950). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3.
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
All of Us Research Program, National Institutes of Health RCV000475413 SCV004844779 likely pathogenic Hypertrophic cardiomyopathy 2023-11-20 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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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, 30847666, 31568572, 33029862, 33495596, Kaam et al. 2019, doi: 10.1038/s41431-019-0404-7, ClinVar SCV000564443.5) or suspected of having 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.
CeGaT Center for Human Genetics Tuebingen RCV000766440 SCV005041894 likely pathogenic not provided 2024-04-01 criteria provided, single submitter clinical testing MYH7: PS4, PM2, PM5:Supporting, PP3

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.