rs727504240

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP2PP3_StrongPP5

The NM_000257.4(MYH7):c.2080C>T(p.Arg694Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23426045-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 264068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 14-23426046-G-A is Pathogenic according to our data. Variant chr14-23426046-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 177627.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=4, Pathogenic=1}. Variant chr14-23426046-G-A is described in Lovd as [Pathogenic]. Variant chr14-23426046-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

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:

AN:

251358

Hom.:

AF XY:

0.0000221

AC XY:

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:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

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:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypertrophic cardiomyopathy

Pathogenic:2

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. -

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

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.99

MutPred

0.77

Gain of catalytic residue at L693 (P = 0);

MVP

0.97

MPC

2.4

ClinPred

0.98

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over