rs121913632

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP3PM1PM5PM2PP1_ModeratePS4

This summary comes from the ClinGen Evidence Repository: The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID:8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). This variant was absent from large population studies (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>C p.Gly741Arg - Variation ID 14098). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PP1_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA012022/MONDO:0005045/002

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

13

6

1

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 5.71

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 13 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.

PM5

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.2221G>T	p.Gly741Trp	missense_variant	20/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2221G>T	p.Gly741Trp	missense_variant	19/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2221G>T	p.Gly741Trp	missense_variant	20/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152214

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

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

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461672

Hom.:

0

Cov.:

33

AF XY:

0.00000138

AC XY:

1

AN XY:

727146

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152214

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74372

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2014	The Gly741Trp variant in MYH7 has been reported in at least 3 individuals with H CM (Arai 1995, Perrot 2005, Pan 2012) and segregated with disease in 4 affected relatives from 2 families. This variant has also been previously identified by o ur laboratory in 5 individuals with HCM. It was absent from large population stu dies. Glycine (Gly) at position 741 is conserved in mammals, though not across evolutionarily distant species (birds and fish). The change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated b y our laboratory. This tool's pathogenic prediction is estimated to be correct 9 4% of the time (Jordan 2011). In addition, another variant at this position (Gly 741Arg) is reported to be disease-causing. In summary, although additional studi es are required to fully establish its clinical significance, the Gly741Trp vari ant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Nov 02, 2018	This MYH7 Gly741Trp variant has been reported in mutliple HCM cases (Arai S, et al., 1995; Perrot A, et al., 2005; Otsuka H, et al., 2012; Santos S, et al., 2012; Pan S, et al., 2012; Kapplinger JD, et al., 2014; Walsh R, et al., 2017), and the variant was shown to segregate with disease in affected family members (Arai S, et al., 1995; Perrot A, et al., 2005). Interestingly, a variant at the same position resulting in a different amino acid change, Gly741Arg, has extensively reported in HCM cases (Fananapazir L, et al., 1993; Richard P, et al., 2003; Van Driest SL, et al., 2004; Song L, et al., 2005; Kaski JP, et al., 2009; Marsiglia JD, et al., 2013; Kapplinger JD, et al., 2014; Walsh R, et al., 2017). The MYH7 Gly741Trp variant is absent in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), and the 1000 genomes project (http://www.1000genomes.org/). We have identified this variant in 5 HCM Probands. All four probands have a family history of disease, but segregation was only possible in 3 of these families and we found this variant to segregate in total of 4 affected first degree family members. In silico tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 15 unrelated probands (PS4), segregates with disease in multiple families (PP1_strong), is located in a mutational hotspot (PM1), is rare in the general population (PM2), affects the same amino acid as another disease-causing variant (PM5), and is predicted to be deleterious by multiple in silico tools (PP3), therefore we classify MYH7 Gly741Trp as 'Pathogenic'. -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Mar 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 741 of the MYH7 protein (p.Gly741Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 8533830, 15856146, 22112859, 22429680, 25935763, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177665). 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. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID: 8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). This variant was absent from large population studies (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>C p.Gly741Arg - Variation ID 14098). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PP1_Moderate; PP3 -

not provided

Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 09, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Gly741Trp (c.2221G>T) The variant has been seen in at least 9 unrelated individuals with HCM with moderately segregation data in one family. Arai et al (1995) reported a Japanese family with four individuals who all had HCM and carried p.Gly741Trp. The authors of that paper refer to an additional Japanese case, reported in a book chapter by Kimura et al (1994). Perrot et al (2005) reported two siblings from a German family who both had HCM and this variant. Santos et al (2012) observed the variant in one of 80 Portuguese patients with HCM. Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). It is not currently listed in ClinVar (as of October 3rd 2014). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging and mutationtaster predicts it to be disease causing. The glycine at codon 741 is conserved across species, as are neighboring amino acids. Two other variants at the same codon have been associated with cardiomyopathy: p.Gly741Arg (Van Driest et al 2004, we consider this variant very likely disease causing), p.Gly741Ala (primary data unavailable). Variants at nearby codons have also been reported in association with cardiomyopathy (p.Ile736Val, p.Ile736Thr, p.Ile736Met, p.Ala742Glu, p.Glu743Asp). Functional studies have shown that another variant at this codon, p.Gly741Arg, confers reduced isometric force generation and decreased velocity of shortening (Lankford et al 1995). In total the variant has not been seen in ~6896 published controls and publicly available population datasets. There is no variation at codon 741 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 1 Oct 2014). The variant is listed in dbSNP (rs121913632), however the only submissions are OMIM and LMM (as of 1 October 2014). The variant is not listed in the 1000 genomes dataset (as of 1 October 2014). The variant was not observed in the following published control samples: 96 (Perrot et al 2005), 100 (Santos et al 2012), 200 (Bos et al 2014). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jan 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2024	Identified in a multiple patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 8533830, 15856146, 23074333, 23283745, 24510615, 27532257, 30025578); 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: 23074333, 27247418, 8533830, 25935763, 21310275, 28606303, 15856146, 23283745, 24510615, 27532257, 24810389, 30025578, 29300372, 28166811, 29369293, 31737537, 32344918, 29907873, 31006259, 32746448, 32894683, 36252119, 37652022, 36243179, 35653365, 35288587, 26914223) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2021

The p.G741W pathogenic mutation (also known as c.2221G>T), located in coding exon 18 of the MYH7 gene, results from a G to T substitution at nucleotide position 2221. The glycine at codon 741 is replaced by tryptophan, 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 variant has been described in several hypertrophic cardiomyopathy (HCM) cohorts and has been observed to co-segregate with disease in families (Arai S et al. Am J Med Genet. 1995;58:267-76; Perrot A et al. J Mol Med. 2005;83:468-77; Bagnall RD et al. J Am Coll Cardiol, 2018 07;72:419-429; Walsh R et al. Genet Med, 2017 02;19:192-203). In addition, another substitution at the same codon, p.G741R (c.2221G>A and c.2221G>C), has been described in multiple individuals with HCM (Fananapazir L et al. Proc Natl Acad Sci U.S.A. 1993;90(9):3993-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Mar 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

30

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

D

LIST_S2

Uncertain

0.96

D

M_CAP

Pathogenic

0.89

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.5

M

MutationTaster

Benign

1.0

D

PrimateAI

Uncertain

0.66

T

PROVEAN

Uncertain

-3.9

D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.72

MutPred

0.78

Gain of catalytic residue at I736 (P = 5e-04);

MVP

0.95

MPC

2.3

ClinPred

1.0

D

GERP RS

4.8

Varity_R

0.93

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: rs121913632; hg19: chr14-23894969;