Submissions for variant NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp)

dbSNP: rs45544633

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151238	SCV000199112	likely pathogenic	Primary dilated cardiomyopathy	2017-08-29	criteria provided, single submitter	clinical testing	The p.Arg1500Trp variant in MYH7 has been reported in the heterozygous state in 2 adults with LVNC and at least 6 adults with DCM (Karkkainen 2004, Jerosch-Hero l 2008, Merlo 2013, Hazebroek 2015, ClinVar Variation ID 164284). It was also id entified in the homozygous state in 1 child with neonatal DCM (GeneDx personal c ommunication). Furthermore, the variant segregated with disease in 2 affected re latives from 1 family (Jerosch-Herol 2008) and was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function (Armel 2010, Wolny 2013). However, these ty pes of assays may not accurately represent biological function. Additionally, th is variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to b e correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1500Trp var iant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232679	SCV000284279	pathogenic	Hypertrophic cardiomyopathy	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1500 of the MYH7 protein (p.Arg1500Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant dilated cardiomyopathy (PMID: 15556047, 18660445, 19412328, 24119082). ClinVar contains an entry for this variant (Variation ID: 164284). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19854198). This variant disrupts the p.Arg1500 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15322983, 19854198, 22155079). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000617211	SCV000737223	likely pathogenic	Cardiovascular phenotype	2024-05-21	criteria provided, single submitter	clinical testing	The p.R1500W variant (also known as c.4498C>T), located in coding exon 30 of the MYH7 gene, results from a C to T substitution at nucleotide position 4498. The arginine at codon 1500 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) cohorts (Kärkkäinen S et al. Eur. J. Heart Fail. 2004;6:861-8; Hershberger RE et al. Clin Transl Sci. 2008;1:21-6; Jerosch-Herold M et al. Am. J. Physiol. Heart Circ. Physiol. 2008;295:H1234-H1242; Merlo M et al. Clin Transl Sci. 2013;6:424-8; Forleo C et al. PLoS ONE. 2017;12:e0181842). In vitro studies suggest that this alteration has an impact on filament formation; however, the same effect was not reproduced in vivo (Armel TZ et al. J. Mol. Cell. Cardiol., 2010 May;48:1007-13; Buvoli M et al. J. Mol. Biol. 2012;415:807-18; Wolny M et al. J. Biol. Chem., 2013 Nov;288:31952-62). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770475	SCV000901918	likely pathogenic	Cardiomyopathy	2017-06-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498700	SCV002810484	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	2021-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770475	SCV004359533	likely pathogenic	Cardiomyopathy	2022-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1500 in the LMM domain in the C-terminal tail region of the MYH7 protein that forms the thick filament backbone and interacts with other proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). In vitro functional studies provide some evidence that this variant may destabilize the MYH7 protein (PMID: 19854198, 22155079, 24047955). This variant has been reported in more than 10 individuals affected with dilated cardiomyopathy (PMID: 15556047, 18660445, 24119082, 26383716, 28750076, 31317183; communication with external laboratories: ClinVar SCV000901918.1 and SCV000737223.3) and in multiple individuals with left ventricular noncompaction cardiomyopathy (communication with external laboratories: ClinVar SCV000199112.4 and SCV000737223.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000151238	SCV004844777	likely pathogenic	Primary dilated cardiomyopathy	2023-11-15	criteria provided, single submitter	clinical testing	The c.4498C>T (p.Arg1500Trp) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in at least seven unrelated individuals affected with Dilated Cardiomyopathy (DCM) (PMID:15556047, 19412328, 24119082, 28750076, 26383716, 32880476, 29540472). This variant is found to segregate with three affected individuals including the proband in one family (PMID: 18660445). Experimental studies have shown that this missense change causes severely decreased thermodynamic stability and affects filament assembly (PMID: 19854198). However, other studies have shown that this variant doesn?t appreciably affect myosin filament formation, myosin heavy chain incorporation into muscle sarcomeres, and myocyte contraction (PMID: 22155079, 24047955). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.836). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 164284). Therefore, the c.4498C>T (p.Arg1500Trp) variant in the MYH7 gene is classified as likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786165	SCV000924859	likely pathogenic	not provided	2016-01-11	no assertion criteria provided	provider interpretation