Submissions for variant NM_000257.4(MYH7):c.431G>A (p.Gly144Asp)

dbSNP: rs730880834

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766398	SCV000208667	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Reported in association with HCM, although detailed clinical information was not provided (Homburger et al., 2016; Maurizi et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018); 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: 27532257, 29300372, 28606303, 29710196, 27247418)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223182	SCV000272048	uncertain significance	not specified	2015-04-10	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly144Asp variant in MYH7 has not been previously reported in individuals with cardiomyop athy and was absent from large population studies. Glycine (Gly) at position 144 is highly conserved in mammals and across evolutionarily distant species and th e change to Aspartic acid (Asp) was predicted to be pathogenic using a computati onal tool clinically validated by our laboratory. This tool's pathogenic predict ion is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Gly144Asp variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001191615	SCV001359501	uncertain significance	Cardiomyopathy	2018-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326905	SCV002627734	uncertain significance	Cardiovascular phenotype	2023-01-09	criteria provided, single submitter	clinical testing	The p.G144D variant (also known as c.431G>A), located in coding exon 3 of the MYH7 gene, results from a G to A substitution at nucleotide position 431. The glycine at codon 144 is replaced by aspartic acid, an amino acid with similar properties. This variant has been identified in hypertrophic cardiomyopathy cohorts; however, clinical details were limited (Maurizi N et al. JAMA Cardiol, 2018 Apr;doi: 10.1001/jamacardio.2018.0789; Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6). 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 available evidence to date, the clinical significance of this alteration remains unclear.
Invitae	RCV002515076	SCV003442789	uncertain significance	Hypertrophic cardiomyopathy	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 144 of the MYH7 protein (p.Gly144Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181302). 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.