rs727504240

Positions:

chr14-23426046-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM1PP3PP1PS4_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

Scores

16

3

1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.72

Variant links:

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]

MYH7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP1

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2080C>T	p.Arg694Cys	missense_variant	19/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2080C>T	p.Arg694Cys	missense_variant	18/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2080C>T	p.Arg694Cys	missense_variant	19/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152202

Hom.:

0

Cov.:

32

show subpopulations

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

show subpopulations

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

show subpopulations

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

show subpopulations

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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+	-	- -

Hypertrophic cardiomyopathy

Pathogenic:4

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	Labcorp Genetics (formerly Invitae), Labcorp	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. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Sep 04, 2024	The heterozygous p.Arg694Cys variant in MYH7 was identified by our study in 1 individual with Laing early-onset distal myopathy (PMID: 32528171). This variant is assumed de novo in the individual, but maternity and paternity have not been confirmed. The p.Arg694Cys variant in MYH7 has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 10563488, 15519027, 18761664, 32369506) and has been identified in 0.007% (2/29608) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504240). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. This variant has also been reported in ClinVar (Variation ID: 177627) and has been interpreted as pathogenic and likely pathogenic by multiple submitters. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg694His, has been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 264068). Multiple variants in the same region as p.Arg694Cys have been reported in association with disease in the literature and ClinVar, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 27532257). The number of missense variants reported in MYH7 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. Although this variant was identified in our study in a proband with Laing early-onset distal myopathy, there is insufficient evidence to also associate the variant with this condition. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PP3_moderate, PM5, PS4_moderate, PP2, PM1_supporting (Richards 2015). -
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

- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504240; hg19: chr14-23895255;