14-23425760-C-G

Position:

chr14-23425760-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PP1PP3PM6PM5PM1PM2PS4

This summary comes from the ClinGen Evidence Repository: The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID:30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). 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>T p.Gly741Trp - Variation ID 177665). 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; PM6; PP1; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA012013/MONDO:0005045/002

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

13

5

2

Clinical Significance

Pathogenic reviewed by expert panel P:12

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 14 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.

PM6

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>C	p.Gly741Arg	missense_variant	20/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2221G>C	p.Gly741Arg	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>C	p.Gly741Arg	missense_variant	20/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

0.00000137

AC:

2

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:

0.0000166

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

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	Oct 16, 2015	The p.Gly741Arg variant has been reported in >10 individuals with HCM, occurred de novo in one of them, and segregated with disease in 3 affected relatives from 2 families (Fananapazir 1993, Malinchik 1997, Richard 2003, Van Driest 2004, So ng 2005, Kaski 2009, LMM unpublished data). It has not been identified in large population studies. This variant was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). In summary, altho ugh additional studies are required to fully establish its clinical significance , this variant is likely pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2221G>C (p.Gly741Arg) variant in MYH7 has been reported in >12 individuals with hypertrophic cardiomyopathy (PS4; PMID:8483915; PMID:15563892; PMID:20031618; PMID:15358028; Partners LMM ClinVar SCV000059430.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 1 proband with hypertrophic cardiomyopathy (PM6; PMID:15563892). This variant segregated with disease in 3 affected individuals (PP1; PMID:8483915; Partners LMM ClinVar SCV000059430.5). 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>T p.Gly741Trp - Variation ID 177665). 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; PM6; PP1; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 31, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 09, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 741 of the MYH7 protein (p.Gly741Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 15358028, 15563892, 20031618, 24093860, 24111713, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14098). 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 disrupts the p.Gly741 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8533830, 15856146). 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. -
Pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Jun 14, 2017	The MYH7 Gly741Arg (c.2221G>C) has been reported in more than 10 unrelated HCM probands and has been found to cosegregate in a few cases (see literature). Song L, et al., (2005), reported 1 HCM where the variant arose de novo. We identified this variant in 1 HCM proband of Middle Eastern descent, with a strong family history of disease in the family, however genetic testing was only possible for one affected sibling who was also found to harbour the variant. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools, SIFT, PolyPhen-2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious. Furthermore functional studies suggest that the variant results in decreased velocity of shortening and reduced isometric force generation (Lankford EB, et al., 1995). 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. Furthermore variant located in the converter region of MYH7 (amino acids 709-777) are predicted to result in worse outcomes (Garcia-Giustiniani D, et al., 2015). Interestingly, a different rare variant at this position (Gly741Trp) has also been classified as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. In summary based on this evidence we classify MYH7 Gly741Arg as 'Pathogenic'. -

Hypertrophic cardiomyopathy 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Oct 04, 2023	ACMG Criteria: PM1, PM2, PS1, PP1, PP3, PM5; Variant was found in a heterozygous state -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1993	- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 12, 2019

- -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 26, 2021

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2021

Not observed in large population cohorts (gnomAD); Published functional studies evaluating the contractile properties of single slow-twitch muscle fibers from patients with this variant demonstrate that G741R results in decreased maximum velocity of fiber shortening and decreased isometric force generation, suggesting this variant has a damaging effect on the protein (Lankford et al., 1995); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 7731997, 24093860, 27532257, 27476098, 31006259, 33642254, 15563892, 20031618, 8483915, 15358028, 12707239, 28246639, 27247418, 24111713, 29300372, 24704860, 32710294, 25935763, 32894683, 7883988) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2018

The p.G741R pathogenic mutation (also known as c.2221G>C), located in coding exon 18 of the MYH7 gene, results from a G to C substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and a different nucleotide substitution (c.2221G>A) resulting in the same amino acid change were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) including a reported de novo occurrence (Fananapazir L, Proc. Natl. Acad. Sci. U.S.A. 1993 May; 90(9):3993-7; Montag J et al. J. Muscle Res. Cell. Motil. 2017 Aug;38(3-4):291-302). The p.G741R alteration has been reported in multiple additional HCM cohorts (Richard P et al. Circulation. 2003;107(17):2227-32; Van Driest SL et al. J Am Coll Cardiol. 2004;44(3):602-10; Song L et al. Clin Chim Acta. 2005;351(1-2):209-16; Kindel SJ et al. J Card Fail. 2012;18(5):396-403; Marsiglia JD et al. Am Heart J. 2013;166(4):775-82; Berge KE et al. Clin Genet 2014;86(4):355-60). In addition, another alteration involving the same amino acid (p.G741W, c.2221G>T) has also been reported in association with HCM (Arai S et al. Am J Med Genet. 1995;58:267-76). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

28

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.86

D

M_CAP

Pathogenic

0.85

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

0.97

D

MutationAssessor

Benign

1.6

L

MutationTaster

Benign

1.0

A

PrimateAI

Uncertain

0.67

T

PROVEAN

Uncertain

-2.6

D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0010

D

Polyphen

0.97

D

Vest4

0.95

MutPred

0.78

Gain of catalytic residue at I736 (P = 0.001);

MVP

0.99

MPC

2.3

ClinPred

0.98

D

GERP RS

4.8

Varity_R

0.83

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;