Submissions for variant NM_000257.4(MYH7):c.2572C>T (p.Arg858Cys)

gnomAD frequency: 0.00003  dbSNP: rs2754158

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000457606	SCV000199179	pathogenic	Hypertrophic cardiomyopathy	2021-02-02	criteria provided, single submitter	clinical testing	The p.Arg858Cys variant in MYH7 has been reported in at least 15 heterozygous individuals with HCM (Ven Driest 2004 PMID:15358028, Mora 2006 PMID:16938236, Uchiyama 2009 PMID:19149795, Funada 2010 PMID:20975235, Bick 2012 PMID:22958901, Marsiglia 2013 PMID:24093860, Berge 2014 PMID:24111713, Bos 2014 PMID:24793961, Li 2015 PMID:26187847, Chiou 2015 PMID:25086479, Walsh 2017 PMID:27532257, Robyns 2020 PMID:31513939) and reportedly occurred as a de novo variant in 1 individual with HCM (Zhao 2017 PMID:28498465). It has also segregated with disease in at least 6 affected relatives (Chiou 2015 PMID:25086479). This variant has also been reported in ClinVar (Variation ID 164324) and in 0.006% (1/16256) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM1, PP1_Moderate, PM6, PP3.
GeneDx	RCV000225738	SCV000208471	likely pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 164324; ClinVar); 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: 24111713, 25086479, 15358028, 29169752, 34542152, 25125180, 26187847, 25937619, 24093860, 27532257, 22958901, 27247418, 19149795, 16938236, 28498465, 24621997, 28971120, 20975235, 31513939, 31589614, 32894683, 33087929, 35653365, 29300372)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201448	SCV000256128	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415053	SCV000492716	likely pathogenic	Myopathy	2015-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000457606	SCV000546275	pathogenic	Hypertrophic cardiomyopathy	2023-12-08	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 858 of the MYH7 protein (p.Arg858Cys). This variant is present in population databases (rs2754158, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 24093860, 28498465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 164324). 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%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc.	RCV000201448	SCV000679785	likely pathogenic	Hypertrophic cardiomyopathy 1	2017-08-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, University of Leuven	RCV000457606	SCV000886788	likely pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000225738	SCV001149186	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198295	SCV001369179	likely pathogenic	Congenital myopathy with fiber type disproportion	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001524491	SCV001734359	pathogenic	Cardiomyopathy	2023-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 858 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16938236, 19149795, 20975235, 24793961, 25086479, 25937619, 27247418, 27532257, 28498465, 28971120, 31513939, 33495597) and has been shown to segregate with disease in a family study (PMID: 25086479). A different missense variant occurring at the same codon, p.Arg858His (ClinVar variation ID: 177696), is known to be pathogenic, indicating that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Revvity Omics, Revvity	RCV000225738	SCV002017850	likely pathogenic	not provided	2021-09-05	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000225738	SCV002502757	likely pathogenic	not provided	2021-09-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453490	SCV002738910	likely pathogenic	Cardiovascular phenotype	2022-11-17	criteria provided, single submitter	clinical testing	The p.R858C variant (also known as c.2572C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2572. The arginine at codon 858 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in individuals with hypertrophic cardiomyopathy (Funada A et al. Circ. J., 2010 Nov;74:2674-80; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Zhao Y et al. Int. J. Mol. Med., 2017 Jul;40:121-129). This alteration was also described to segregate with the disease in one family (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002505152	SCV002814102	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	2022-04-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001524491	SCV003838755	pathogenic	Cardiomyopathy	2021-09-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333032	SCV004041297	likely pathogenic	Myosin storage myopathy	2023-08-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000201448	SCV004041370	likely pathogenic	Hypertrophic cardiomyopathy 1	2023-08-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333029	SCV004041371	likely pathogenic	Dilated cardiomyopathy 1S	2023-08-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333031	SCV004041405	likely pathogenic	Myopathy, myosin storage, autosomal recessive	2023-08-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333030	SCV004041498	likely pathogenic	MYH7-related skeletal myopathy	2023-08-30	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003448270	SCV004176199	likely pathogenic	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1S	2023-06-14	criteria provided, single submitter	clinical testing	The c.2572C>T p.(Arg858Cys) variant in MYH7 has previously been reported in multiple individuals with hypertrophic cardiomyopathy in heterozygous state (PMID: 15358028, 16938236, 19149795, 24093860, 20975235, 28498465, 34542152, 35653365), and has been deposited in ClinVar database as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 164324]. The c.2572C>T variant is observed in 14 alleles (~0.0023% minor allele frequency with 0 homozygotes) 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. The c.2572C>T variant in MYH7 is located in exon 22 of this 40-exon gene and predicted to replace a moderately conserved arginine amino acid with cysteine at position 858 in the coiled coil domain (839-1935aa; Uniprot ID: P12883) of the encoded protein. In silico predictions are favor of damaging effect for the p.(Arg858Cys) variant [REVEL = 0.631]; however, there are no functional studies to support or refute these predictions. Another missense substitution affecting the same protein residue c.2573G>C, p.(Arg858Pro) has been reported in the literature [PMID: 27247418, 27532257] and in ClinVar [ClinVar ID: 520277] in individuals with hypertrophic cardiomyopathy. Based on available evidence this c.2572C>T, p.(Arg858Cys) variant identified in MYH7 is classified as Likely Pathogenic