rs727504240

Positions:

• chr14-23426046-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM1 PP3 PP1 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2080C>T (p.Arg694Cys) has been identified in at least 15 individuals with HCM, including 3 who also carried other potentially disease-causing variants (PS4_Moderate; Andersen 1999 PMID:10563488; Havndrup 2003 PMID:12566107; Andersen 2004 PMID:15114369; Van Driest 2004 PMID:15358028; Van Driest 2004 PMID:15519027; Olivotto 2008 PMID:18533079; Ho 2009 PMID:20031602; Jensen 2013 PMID:23197161; Witjas-Paalberends 2013 PMID:23674513; Coppini 2014 PMID:25524337; Alfares 2015 PMID:25611685; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry pers. comm; GeneDx pers. comm; Invitae pers. comm; LMM pers. comm). This variant segregated with disease in 4 affected relatives with HCM from 2 families (PP1; Andersen 2004 PMID:15114369; GeneDx pers. comm.). This variant was identified in 0.001% (FAF 95% CI; 4/113682) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1, PM2, PM1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA011642/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 4.72

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2080C>T	p.Arg694Cys	missense_variant	19/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2080C>T	p.Arg694Cys	missense_variant	18/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2080C>T	p.Arg694Cys	missense_variant	19/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251358 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2022	Identified in several individuals with HCM in published literature, though some of these individuals also harbored reportedly pathogenic variants in other HCM-related genes (Andersen et al., 1999; Van Driest et al., 2004; Olivotto et al., 2008; Walsh et al., 2017; Mattivi et al., 2020); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for cardiomyopathy genetic testing at GeneDx, and it was observed to segregate with cardiomyopathy in at least one family member; Not observed at significant frequency in large population cohorts (gnomAD); 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: 26688388, 21310275, 34542152, 31737537, 32528171, 23197161, 24928957, 18533079, 18761664, 20031602, 25524337, 12566107, 15114369, 15519027, 27532257, 15358028, 25611685, 20819418, 28606303, 27247418, 23674513, 29300372, 32894683, 32369506, 31323898, 10563488) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 19, 2019	The p.Arg694Cys variant in MYH7 has been reported in at least 11 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Andersen 1999 and 2004, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, GeneDx pers comm, LMM data). At least 4 individuals carried additional likely disease causing variants in the MYBPC3 gene (Van Driest 2004, GeneDx pers comm). In addition, this variant has been identified in 5/251358 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variant ID: 177627). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant lies in the head region of the protein, and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Moderate, PM1, PM2, PP3, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 10, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 694 of the MYH7 protein (p.Arg694Cys). This variant is present in population databases (rs727504240, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10563488, 12566107, 15114369, 15519027, 22811549, 23674513, 25611685, 27247418, 27532257, 31737537, 32894683; Invitae). ClinVar contains an entry for this variant (Variation ID: 177627). 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. 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). This variant disrupts the p.Arg694 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 12974739, 20819418), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Dec 27, 2023	The c.2080C>T (p.Arg694Cys) variant in MYH7 gene, that encodes for myosin heavy chain 7, has been identified in several (>10) unrelated individuals affected with the consistent phenotype of hypertrophic cardiomyopathy (HCM) (PMID:15358028, 23674513, 25611685, 27532257, 32894683, 22811549, 32369506, 27247418, 24793961, 31737537) and segregated with disease in three affected individuals including the proband in one family (PMID: 10563488). This variant lies in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations and missense variants in this region are statistically more likely to be disease-associated (PMID:27532257, 27247418). In-silico computational prediction tools suggest that the p.Arg694Cys variant may have deleterious effect on the protein function (REVEL score: 0.81). This variant is rare (5/251358 chromosomes; 0.001989%) in the general population database, gnomAD. It is interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ID: 177627). Another missense substitution affecting the same amino acid, p.Arg694His, has been reported in several (>10) individuals with HCM and classified as likely pathogenic/pathogenic by several submitters in ClinVar (ID: 264068). Therefore, the c.2080C>T (p.Arg694Cys) variant in the MYH7 gene is classified as likely pathogenic. -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 04, 2022

This missense variant replaces arginine with cysteine at codon 694 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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 at least 15 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18533079, 23674513, 24793961, 25524337, 27247418, 27532257, 32228044, 32369506), including 5 of them who also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 18533079, 32228044). It has been shown that this variant segregates with disease in 5 affected individuals in a family (PMID: 10563488, 15114369, 19035361). This variant has also been reported in an individual affected with unexplained limb-girdle weakness (PMID: 32528171). This variant has been identified in 5/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2022

The p.R694C variant (also known as c.2080C>T), located in coding exon 17 of the MYH7 gene, results from a C to T substitution at nucleotide position 2080. The arginine at codon 694 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 multiple individuals with hypertrophic cardiomyopathy (HCM), including some cases with additional cardiac variants detected (Andersen PS et al. Eur. J. Hum. Genet., 2004 Aug;12:673-7; Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ho CY et al. Circulation, 2018 10;138:1387-1398). Another alteration at the same codon, p.R694H c.2081G>A, have been reported in several patients from HCM (Erdmann J et al. Clin Genet. 2003;64(4):339-49; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60; Lopes LR et al. Heart. 2015;101(4):294-301; GeneDx pers. comm.; Invitae pers. comm.; Ambry internal data).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. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Dec 12, 2018

- -

MYH7-related skeletal myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Arg694Cys variant in MYH7 has been identified by our project in one individual with distal myopathy. This variant has been reported in at least 11 individuals with HCM, and was found to segregate with disease in 3 affected relatives across 2 families (Andersen 1999, Van Driest 2004, Witjas-Paalberends 2013, Alfares 2015, pers comm). However, at least 4 of those individuals, including the individual reported by Van Driest, also carried an additional likely disease causing variant in the MYBPC3 gene (Van Driest 2004, pers comm). Additionally, this variant has been reported in ClinVar by two seperate clinical laboratories that both currently classify it as a Variant of Uncertain Significance (LMM pers comm, Variant ID: 177627). Other missense variants at the same residue (Arg694Leu, Arg694His) have been reported in the Human Gene Mutation Database in association with cardiomyopathy, however they are both of uncertain significance (Stenson et al., 2014). This variant has been identified in 0.01% (1/17,248) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504240). In summary, the clinical significance of the p.Arg694Cys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.77		Gain of catalytic residue at L693 (P = 0);
MVP		0.97
MPC		2.4
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504240; hg19: chr14-23895255;