Submissions for variant NM_000257.4(MYH7):c.4030C>T (p.Arg1344Trp)

dbSNP: rs727504352

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766454	SCV000208563	uncertain significance	not provided	2017-04-11	criteria provided, single submitter	clinical testing	p.Arg1344Trp (CGG>TGG): c.4030 C>T in exon 30 of the MYH7 gene (NM_000257.2). The Arg1344Trp mutation in the MYH7 gene has been reported in one individual with DCM (Lakdawala N et al., 2012). Arg1344Trp results in a non-conservative amino acid substitution of a positively charged Arginine with a non-polar Tryptophan at a position that is well conserved across species. In silico analysis predicts Arg1344Trp is probably damaging to the protein structure/function. A mutation in a nearby residue (Thr1351Met, Glu1356Lys) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Arg1344Trp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, Arg1344Trp in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001186002	SCV001352327	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1344 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 27532257) and in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant has been identified in 4/250960 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.
Invitae	RCV001850114	SCV002147139	uncertain significance	Hypertrophic cardiomyopathy	2022-01-28	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 1344 of the MYH7 protein (p.Arg1344Trp). This variant is present in population databases (rs727504352, gnomAD 0.007%). This missense change has been observed in individual(s) with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 22464770, 27532257). ClinVar contains an entry for this variant (Variation ID: 177839). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483336	SCV002788840	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
3billion	RCV003152685	SCV003841884	uncertain significance	Hypertrophic cardiomyopathy 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.23). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYH7 related disorder (PMID: 22464770). A different missense change at the same codon (p.Arg1344Gln) has been reported to be associated with MYH7 related disorder (ClinVar ID: VCV000208597 / PMID: 24093860). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003298164	SCV003993386	uncertain significance	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.R1344W variant (also known as c.4030C>T), located in coding exon 28 of the MYH7 gene, results from a C to T substitution at nucleotide position 4030. The arginine at codon 1344 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in 1 patient with dilated cardiomyopathy (DCM) in a large study of pathogenicity of Mendelian variants in cardiomyopathy patients, but clinical details are limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203). 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.
All of Us Research Program, National Institutes of Health	RCV001186002	SCV004821095	uncertain significance	Cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1344 of the MYH7 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 24093860, 27532257) and in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant has been identified in 4/250960 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154475	SCV000204144	uncertain significance	not specified	2015-10-16	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory