Submissions for variant NM_000257.4(MYH7):c.4135G>A (p.Ala1379Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516202

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000629005	SCV000059538	pathogenic	Hypertrophic cardiomyopathy	2013-08-23	criteria provided, single submitter	clinical testing	The p.Ala1379Thr variant in MYH7 has been reported in 5 families with HCM, segre gated with disease in >15 affected relatives from 4 families (Blair 2002, Richar d 2003, Zou 2013, LMM data) and was absent from large population studies. This v ariant was predicted to be pathogenic using a computational tool clinically vali dated by our laboratory. This tool's pathogenic prediction is estimated to be co rrect 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon s egregation studies and absence from controls.
GeneDx	RCV000505712	SCV000208572	pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	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: 25961035, 28166811, 30466861, 23283745, 16918501, 11861410, 22199023, 21310275, 12707239, 27532257, 27247418, 28790153, 28615295, 33631351, 27387980, 33673806, 32894683, 33087929, 27535533, 11861413, 26582918, 35935646, 34076677)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000629005	SCV000212637	pathogenic	Hypertrophic cardiomyopathy	2018-08-23	criteria provided, single submitter	research	MYH7 Ala1379Thr has previously been identified in multple HCM cases (Walsh R et al., 2017; Zou Y et al., 2013; Richard P et al., 2003; Blair E et al., 2002). Familial analysis by Blair E. et al. (2002) demonstrated strong segregation of this variant with disease phenotype. We have detected this variant in 4 unrelated HCM families, 3 of which were reported previously (Ingles J et al., 2017; Burns et al., 2017) and segregated to an additional 3 affected family members in one family. Furthermore, this variant is absent in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) and 1000 genomes project (http://www.1000genomes.org/). In silico tools SIFT, MutationTaster and PolyPhen-2 predict that the variant is deleterious. More specifically, a tool designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts this MYH7 Ala1379Thr variant to be "Pathogenic". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant has been identified in more than 10 unrelated probands (PS4_Strong), has strong segregation data (PP1_Strong), is rare in the general population (PM2) and in silico tools predict that it is deleterious (PP3), therefore we classify MYH7 Ala1379Thr as 'pathogenic'.
Center for Medical Genetics Ghent, University of Ghent	RCV000162337	SCV000299237	likely pathogenic	Hypertrophic cardiomyopathy 1	2016-02-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619392	SCV000737001	pathogenic	Cardiovascular phenotype	2023-01-25	criteria provided, single submitter	clinical testing	The p.A1379T pathogenic mutation (also known as c.4135G>A), located in coding exon 28 of the MYH7 gene, results from a G to A substitution at nucleotide position 4135. The alanine at codon 1379 is replaced by threonine, an amino acid with some similar properties. This variant was reported to segregate with hypertrophic cardiomyopathy (HCM) or related features in multiple individuals across three HCM proband-identified families, and has also been detected in additional HCM cohorts (Blair E et al. Circ Res. 2002;90:263-9; Zou Y et al. Mol Biol Rep. 2013;40:3969-76; Richard P et al. Circulation. 2003;107:2227-32; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000629005	SCV000749915	pathogenic	Hypertrophic cardiomyopathy	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1379 of the MYH7 protein (p.Ala1379Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11861413, 12707239, 23283745, 27247418, 27532257, 28790153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42993). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035887	SCV001337987	pathogenic	Primary familial hypertrophic cardiomyopathy	2020-01-27	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.4135G>A (p.Ala1379Thr) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of 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 251464 control chromosomes (gnomAD). c.4135G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Richard_2003, Blair_2002, Ross_2017). Blair_2002 reported that this variant segregated with disease in three unrelated families and was not present in 200 control chromosomes. These data indicate that the variant is very likely to be associated with disease. At least one publication, Flashman_2007, reports this variant has no effect on interaction with C10 of cMyBP-C. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149622	SCV003838748	pathogenic	Cardiomyopathy	2021-08-20	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000035887	SCV000188802	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2013-10-16	no assertion criteria provided	clinical testing