Submissions for variant NM_000257.4(MYH7):c.5458C>T (p.Arg1820Trp)

dbSNP: rs145734640

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV003320122	SCV001842654	uncertain significance	Myosin storage myopathy	2021-06-16	reviewed by expert panel	curation	The c.5458C>T (p.Arg1820Trp) variant in MYH7 has been identified in the homozygous state in 2 brothers with myosin storage myopathy exhibiting scapuloperoneal and respiratory weakness as well as dilated cardiomyopathy (Yüceyar 2015 PMID:25666907); however, this data is insufficient to apply the PS4 criterion. This variant was identified in 0.00027% (FAF 95% CI; 2/129152) of Non-Finnish European chromosomes, 0.00142% (FAF 95% CI; 2/24966) of African chromosomes, and 1/19954 of East Asian chromosomes by gnomAD v2.1.1 (PM2; http://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 myosin storage myopathy and cardiomyopathy. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PP3
GeneDx	RCV000158703	SCV000208638	likely pathogenic	not provided	2014-02-20	criteria provided, single submitter	clinical testing	p.Arg1820Trp (CGG>TGG): c.5458 C>T in exon 37 of the MYH7 gene (NM_000257.2). The Arg1820Trp variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg1820Trp results in a non-conservative amino acid substitution of positively charged Arginine residue with a non-polar Tryptophan residue at a position that is conserved in mammals. In silico analysis predicts Arg1820Trp is probably damaging to the protein structure/function. Mutations in nearby residues (Glu1829Gly, Arg1832Cys) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The Arg1820Trp variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.In summary, while Arg1820Trp is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM-CRDM panel(s).
Eurofins Ntd Llc (ga)	RCV000158703	SCV000344616	uncertain significance	not provided	2016-08-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685507	SCV000812990	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-22	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 1820 of the MYH7 protein (p.Arg1820Trp). This variant is present in population databases (rs145734640, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal recessive MYH7-related conditions (PMID: 25666907). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181282). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002345540	SCV002650516	uncertain significance	Cardiovascular phenotype	2022-05-06	criteria provided, single submitter	clinical testing	The p.R1820W variant (also known as c.5458C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5458. The arginine at codon 1820 is replaced by tryptophan, an amino acid with dissimilar properties.This alteration has been reported in the homozygous state in 2 siblings with myosin storage myopathy, one of whom has been diagnosed with dilated cardiomyopathy (Yüceyar N et al. Neuromuscul. Disord., 2015 Apr;25:340-4). This variant has also been reported in an electronic medical record exome cohort with limited clinical details provided (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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484981	SCV002782510	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
OMIM	RCV000172878	SCV000223868	pathogenic	Myopathy, myosin storage, autosomal recessive	2015-04-01	no assertion criteria provided	literature only