Submissions for variant NM_000257.4(MYH7):c.5305C>A (p.Leu1769Met)

gnomAD frequency: 0.00004  dbSNP: rs139222507

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001040988	SCV001976460	uncertain significance	Hypertrophic cardiomyopathy	2021-08-25	reviewed by expert panel	curation	The c.5305C>A (p.Leu1769Met) variant in MYH7 has been reported in 5 individuals with HCM, including 1 individual with an additional variant in another gene that may contribute to their disease (PS4_Supporting; Girolami 2006 PMID:16858239; Santos 2012 PMID:22429680; GeneDx pers. comm.), as well as in 1 individual with DCM (Stanford Center for Inherited Cardiovascular Disease, ClinVar SCV000280363.1), and 3 individuals with other cardiac phenotypes (1 with syncope and VT, 1 with unspecified cardiomyopathy, and 1 with dysplastic pulmonary valve and stenosis; GeneDx pers. comm.; Mayo Clinic Laboratories pers. comm.). This variant was identified in 0.002% (FAF 95% CI; 6/129192) of European chromosomes in 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, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.
Invitae	RCV001040988	SCV001204582	uncertain significance	Hypertrophic cardiomyopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1769 of the MYH7 protein (p.Leu1769Met). This variant is present in population databases (rs139222507, gnomAD 0.005%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 16858239, 22429680). ClinVar contains an entry for this variant (Variation ID: 161323). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001182017	SCV001347331	uncertain significance	Cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 1769 of the MYH7 protein. Computational prediction suggests that this variant may have 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 16858239, 18533079, 22429680). This variant has been identified in 7/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002483291	SCV002788828	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223890	SCV003817718	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148702	SCV000190431	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223890	SCV000280363	likely pathogenic	not provided	2014-03-26	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Including this patient’s case of DCM, this variant has been seen in 1 case of DCM and 1 case of HCM. No segregation data is available. Girolami et al (2006) found the p.Leu1769Met variant in one individual with HCM. No segregation data was reported. No other variants have been reported at codon 1769, however, variants at nearby codons (p. Ala1766Thr, p. Glu1768Lys) have been reported in association with cardiomyopathy (Klassen et al 2008, Van Driest et al 2004). This variant is predicted to be “probably damaging” by PolyPhen-2 analysis. Leucine is completely conserved across all vertebrate species at position 1769. This variant substitutes a nonpolar, neutral amino acid (Leu) with a nonpolar, neutral amino acid (Met). Girolami et al (2006) did not identify the variant in 100 presumably healthy controls (presumably from individuals of Italian ancestry). GeneDx has not observed this variant in 200 control individuals of Caucasian and African American ancestry, for a total of 300 controls.