Submissions for variant NM_000257.4(MYH7):c.5494C>T (p.Arg1832Cys)

dbSNP: rs201865159

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000148701	SCV000050865	uncertain significance	Primary dilated cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466702	SCV000546279	uncertain significance	Hypertrophic cardiomyopathy	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1832 of the MYH7 protein (p.Arg1832Cys). This variant is present in population databases (rs201865159, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19293840). ClinVar contains an entry for this variant (Variation ID: 161322). 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. 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.
GeneDx	RCV000478825	SCV000565295	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	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: 25637381, 21424860, 21310275, 23299917, 23861362, 21839045, 22337857, 34426522, 19293840, 30847666, 34542152)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000478825	SCV000609819	uncertain significance	not provided	2017-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177578	SCV001341815	uncertain significance	Cardiomyopathy	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1832 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 an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 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.
Ambry Genetics	RCV002345457	SCV002650068	uncertain significance	Cardiovascular phenotype	2024-11-27	criteria provided, single submitter	clinical testing	The p.R1832C variant (also known as c.5494C>T), located in coding exon 35 of the MYH7 gene, results from a C to T substitution at nucleotide position 5494. The arginine at codon 1832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in an individual with dilated cardiomyopathy (Møller DV et al. Eur J Hum Genet. 2009 Oct;17:1241-9), and in an individual with hypertrophic cardiomyopathy who also had a frameshift mutation in MYBPC3 (Maron BJ et al. Heart Rhythm. 2012 Jan;9:57-63). This amino acid position is well 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	RCV002492544	SCV002793289	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	2021-11-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000478825	SCV003817762	uncertain significance	not provided	2022-03-16	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003335132	SCV004046614	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1S	2022-11-08	criteria provided, single submitter	clinical testing	The c.5494C>T variant in MYH7 has previously been reported in one individual with idiopathic dilated cardiomyopathy [PMID: 19293840] and it has been deposited in ClinVar [ClinVar ID: 161322] as variant of uncertain significance by multiple submitters. The c.5494C>T variant is observed in 14 alleles (~0.002% minor allelefrequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, which might include individuals with adult onset cardiac phenotypes. The c.5494C>T variant in MYH7 is located in exon 37 of this 40-exon gene, and is predicted to replace an evolutionarily conserved arginine amino acid with cysteine at position 1832 (p.(Arg1832Cys) in the C-terminalrod domain [PMID:35854315] of the encoded protein. In silico predictions provide supporting evidence for damaging effect for the p.(Arg1832Cys) variant [CADD v1.6= 27.4, REVEL = 0.767]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.5494C>Tp.(Arg1832Cys) variant identified in MYH7 is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001177578	SCV004814350	uncertain significance	Cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1832 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 an individual affected with dilated cardiomyopathy (PMID: 19293840) and in two siblings affected with skeletal myopathy and left ventricular non-compaction (Moore et al., 2018). This variant has been observed in an individual with hypertrophic cardiomyopathy, who also carried a pathogenic mutation in the MYBPC3 gene (PMID: 21839045). This variant has been identified in 9/250790 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782253	SCV005394274	uncertain significance	not specified	2024-09-26	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5494C>T (p.Arg1832Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250790 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5494C>T has been reported in the literature in an individual(s) affected with Dilated Cardiomyopathy (e.g. Moller_2009). This result does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19293840). ClinVar contains an entry for this variant (Variation ID: 161322). Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148701	SCV000190430	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000478825	SCV002034097	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000478825	SCV002034546	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000478825	SCV002037246	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000478825	SCV002037676	uncertain significance	not provided		no assertion criteria provided	clinical testing