Submissions for variant NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met)

gnomAD frequency: 0.00001  dbSNP: rs397516201

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000552931	SCV000564449	pathogenic	Hypertrophic cardiomyopathy	2021-11-23	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >30 individuals with HCM (PS4; Richard 2003 PMID: 12707239; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Millat 2010 PMID: 20624503; Witjas-Paalberends 2013 PMID: 23674513; Berge 2014 PMID: 24111713; Helms 2014 PMID: 25031304; Adler 2016 PMID: 26743238; Montag 2017 PMID: 29101517; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >10 affected relatives with HCM in at least 4 families (PP1_strong; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; LMM pers. comm.). This variant was identified in 0.0009% (1/113754) of European chromosomes by gnomAD v2.1.1 (PM2; https://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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_Strong; PM2; PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000552931	SCV000059537	pathogenic	Hypertrophic cardiomyopathy	2022-03-07	criteria provided, single submitter	clinical testing	The p.Thr1377Met variant in MYH7 has been reported in > 35 individuals with HCM (Richard 2003 PMID: 12707239, Van Driest 2004 PMID: 15358028, Girolami 2006 PMID: 16858239, Fokstuen 2008 PMID: 18409188, Olivotto 2008 PMID: 18533079, Millat 2010 PMID: 20624503, Foksteun 2011 PMID: 21239446, Witjas-Paalberends 2013 PMID: 223674513, Adler 2014 PMID: 26743238, Berge 2014 PMID: 24111713, Helms 2014 PMID: 25031304, Kapplinger 2014 PMID: 24510615, Walsh 2016 PMID: 27532257, Song 2017 PMID: 28202948, Perez-Sanchez 2018 PMID: 28687478, Wang 2018 PMID: 29343710, LMM data). This variant has also been shown to segregate in >10 relatives from 7 families, (Perez-Sanchez 2018 PMID: 28687478, Wang 2018 PMID: 29343710, LMM data). It has also been identified in 0.0009% (1/113754) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Thr1377Met variant may impact the protein. Moreover, this variant was classified as Pathogenic on February 25, 2019 by the ClinGen-approved Cardiomyopathy Variant Curation expert panel (Variation ID 42992). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2_supporting, PP3.
GeneDx	RCV000518840	SCV000208571	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Classified as pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert (Clinvar; Variation ID: 42992); Not observed at 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: 16352453, 15358028, 20800588, 25031304, 18409188, 20624503, 21239446, 24835277, 18533079, 23674513, 12707239, 24111713, 24510615, 16858239, 28971120, 27247418, 27532257, 28202948, 29988065, 28687478, 29101517, 29300372, 26743238, 27688314, 30165862, 30665703, 30972196, 29169752, 24093860, 32344918, 30297972, 33673806, 33407484, 32894683, 33658040, 35626289, 35653365, 35208637, 32492895, 29343710)
Blueprint Genetics	RCV000208315	SCV000264090	pathogenic	Primary familial hypertrophic cardiomyopathy	2015-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552931	SCV000623712	pathogenic	Hypertrophic cardiomyopathy	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1377 of the MYH7 protein (p.Thr1377Met). This variant is present in population databases (rs397516201, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12707239, 16858239, 18409188, 20800588, 24111713, 25031304, 27247418, 27532257, 32344918). ClinVar contains an entry for this variant (Variation ID: 42992). 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%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000617360	SCV000739952	pathogenic	Cardiovascular phenotype	2021-09-08	criteria provided, single submitter	clinical testing	The p.T1377M pathogenic mutation (also known as c.4130C>T), located in coding exon 28 of the MYH7 gene, results from a C to T substitution at nucleotide position 4130. The threonine at codon 1377 is replaced by methionine, an amino acid with similar properties. This variant has been previously detected in numerous hypertrophic cardiomyopathy cohorts (Richard P et al. Circulation. 2003;107(17):2227-32 (reported as c.19222C>T); Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Olivotto I et al. Mayo Clin Proc. 2008;83(6):630-8; Millat G et al. Eur J Med Genet. 2010;53:261-7; Fokstuen S et al. J. Med. Genet. 2011;48:572-6; Berge KE et al. Clin Genet. 2014;86(4):355-60; Walsh R et al. Genet. Med. 2017;19:192-203). In addition, this alteration has been shown to segregate with disease in a large Chinese family and has been reported to segregate with disease in several other families (Pérez-Sánchez I et al. Rev Esp Cardiol (Engl Ed), 2018;71:146-154; Wang J et al. Sci Rep, 2018;8:973). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV004528172	SCV000923601	pathogenic	MYH7-related disorder	2023-12-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171198	SCV001333895	pathogenic	Cardiomyopathy	2023-06-15	criteria provided, single submitter	clinical testing
3billion	RCV001807755	SCV002058764	pathogenic	Hypertrophic cardiomyopathy 1	2022-01-03	criteria provided, single submitter	clinical testing	The variant was co-segregated with Cardiomyopathy, hypertrophic, 1 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 12707239, 27247418, 25031304, 20800588, 18409188, 16858239, 24111713, 27532257) (PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 25031304, 18533079, 23674513, 27532257, 21239446, 20624503, 16858239, 12707239, 30297972, 24093860, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000518840	SCV002497697	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	MYH7: PP1:Moderate, PS4:Moderate, PP2, PP3
Fulgent Genetics, Fulgent Genetics	RCV002504879	SCV002814831	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-04-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000518840	SCV004226882	pathogenic	not provided	2018-10-08	criteria provided, single submitter	clinical testing	PP1_strong, PP2, PP3, PM2_supporting, PS4
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000518840	SCV005199389	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000518840	SCV001743719	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000518840	SCV001924160	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000518840	SCV001931913	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000518840	SCV001954216	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000518840	SCV001975765	pathogenic	not provided		no assertion criteria provided	clinical testing