rs121913650

Positions:

chr14-23415652-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3PS4_ModeratePP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.5134C>T (p.Arg1712Trp) variant in MYH7 has been reported in the heterozygous state in at least 13 individuals with HCM, 2 of whom also had additional variants in other HCM-associated genes (PS4_Moderate; Hougs 2005 PMID:15483641; Gruner 2011 PMID:21511876; Jensen 2013 PMID:23197161; Hagen 2013 PMID:24498601; Mu 2019 https://www.actamedicamediterranea.com/archive/2019/medica-5/pathogenic-mutation-detection-and-correlation-analysis-between-genotype-and-phenotype-of-familial-hypertrophic-cardiomyopathy-in-chinese-han-nationality/pdf; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in at least 6 affected relatives from 4 families (PP1_Moderate; Hougs 2005 PMID:15483641; Mu 2019; Ambry pers comm.; Centenary Institute Sydney pers comm.). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). Data from the gnomAD population database (v2.1.1) is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (PM2; http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). 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. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate; PM2; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA015719/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 0.178

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:

ENSG00000258444 (HGNC:):

ENSG00000258444 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS4

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.5134C>T	p.Arg1712Trp	missense_variant	35/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.5134C>T	p.Arg1712Trp	missense_variant	34/39		NP_001393933.1
MHRT	NR_126491.1 linkuse as main transcript	n.84G>A		non_coding_transcript_exon_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.5134C>T	p.Arg1712Trp	missense_variant	35/40	1	NM_000257.4	ENSP00000347507.3		P12883
ENSG00000258444	ENST00000557368.1 linkuse as main transcript	n.173G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This missense variant replaces arginine with tryptophan at codon 1712 in the LMM domain 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 individuals affected with hypertrophic cardiomyopathy (PMID: 15483641, 23197161, 24498601, 25892673, 28790153, 30297972, doi:10.19193/0393-6384_2019_5_383). Some of these individuals also carried a mitochondrial variant in the MT-CYB gene (PMID: 24498601). It has been shown that this variant segregates with disease in multiple affected individuals across two families (PMID: 24498601, doi:10.19193/0393-6384_2019_5_383). This variant has also been reported in homozygous state in two siblings affected with recessive myopathy with no cardiac involvement; both heterozygous parents were unaffected (PMID: 31130376). A different variant occurring at the same codon, p.Arg1712Gln, is a well documented pathogenic mutation (Clinvar variation ID: 36642), indicating that arginine at this position is important for MYH7 protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 14, 2020	The p.Arg1712Trp variant in MYH7 has been reported in the heterozygous state in at least 6 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 6 affected individuals from two families (Hougs 2005 PMID:15483641, Gruner 2011 PMID:21511876, Jensen 2013 PMID:23197161, Hagen 2013 PMID:24498601, Mu 2019, LMM data). One of these individuals also carried another disease-causing variant in another HCM gene (Gruner 2011 PMID:21511876). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). This variant been reported by other clinical laboratories in ClinVar (Variation ID 14118). Data from the gnomAD population database is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Beecroft 2019 PMID:31130376) and computational prediction tools and conservation analysis are consistent with pathogenicity. An additional variant involving this codon (p.Arg1712Gln) has been identified in individuals with HCM and is classified as likely pathogenic by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564455.2). 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_Supporting, PP1_Moderate, PM2, PS3_Supporting, PP3, PM5_Supporting. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Jun 16, 2021	The c.5134C>T (p.Arg1712Trp) variant in MYH7 has been reported in the heterozygous state in at least 13 individuals with HCM, 2 of whom also had additional variants in other HCM-associated genes (PS4_Moderate; Hougs 2005 PMID:15483641; Gruner 2011 PMID:21511876; Jensen 2013 PMID:23197161; Hagen 2013 PMID:24498601; Mu 2019 https://www.actamedicamediterranea.com/archive/2019/medica-5/pathogenic-mutation-detection-and-correlation-analysis-between-genotype-and-phenotype-of-familial-hypertrophic-cardiomyopathy-in-chinese-han-nationality/pdf; Ambry pers. comm.; Centenary Institute Sydney pers. comm.; CHEO pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with HCM in at least 6 affected relatives from 4 families (PP1_Moderate; Hougs 2005 PMID:15483641; Mu 2019; Ambry pers comm.; Centenary Institute Sydney pers comm.). This variant has also been identified in the homozygous state in 2 siblings from a consanguineous family with myopathy and normal cardiac function (Beecroft 2019 PMID:31130376). Data from the gnomAD population database (v2.1.1) is insufficient to assess the frequency of this variant; however, this variant is absent from the ExAC database (PM2; http://gnomad.broadinstitute.org; http://exac.broadinstitute.org). 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. ACMG/AMP Criteria applied: PS4_Moderate; PP1_Moderate; PM2; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 15, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1712 of the MYH7 protein (p.Arg1712Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15483641; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14118). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg1712 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18403758, 21511876, 23785128, 24510615, 27247418, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analyses support that this missense variant has a deleterious effect on protein structure/function and suggest this variant may impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 24498601, 23197161, 19035361, 25961035, 15483641, 32710294, 34691145, 36243179, 36264615, 32894683, Mu_2019_article, 21511876, 31130376) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2023	PP1_moderate, PP3, PM2, PM5, PS3_supporting, PS4_moderate -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University

Jun 01, 2023

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2024

The p.R1712W variant (also known as c.5134C>T), located in coding exon 33 of the MYH7 gene, results from a C to T substitution at nucleotide position 5134. The arginine at codon 1712 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in several hypertrophic cardiomyopathy (HCM) cohorts and individuals reported to have HCM (Hougs L et al. Eur. J. Hum. Genet. 2005;13:161-5; Glotov AS et al. Clin. Chim. Acta. 2015;446:132-40; Burns C et al. Circ Cardiovasc Genet. 2017;10:e001666; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Ambry internal data). In one family, both this alteration and an alteration in MT-CYB (p.C93Y) were observed to segregate with disease (Hagen CM et al. Mol Genet Genomic Med. 2013;1:54-65). This alteration has also been reported in the homozygous state in siblings with myopathy (Beecroft SJ et al. Neuromuscul. Disord., 2019 Jun;29:456-467). Another variant impacting this codon (p.R1712Q) has also been reported in association with HCM (Morita H et al. N. Engl. J. Med. 2008;358:1899-908). 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. -

MYH7-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The MYH7 c.5134C>T variant is predicted to result in the amino acid substitution p.Arg1712Trp. This variant was reported to segregate in families and other unrelated individuals with hypertrophic cardiomyopathy (Hougs et al. 2005. PubMed ID: 15483641; Supp. Table 1 in Ho et al. 2018. PubMed ID: 30297972; Hagen et al. 2013. PubMed ID: 24498601; Supp. Table 2 in Burns et al. 2017. PubMed ID: 28790153). This variant was also reported in the homozygous state in two siblings with features of a congenital myopathy (Beecroft et al. 2019. PubMed ID: 31130376). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has also been reported as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/14118/). This variant is interpreted as likely pathogenic. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

4.2

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MutPred

0.58

Loss of disorder (P = 0.0615);

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

4.5

Varity_R

0.54

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.38

Position offset: 6

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