chr14-23425760-C-T

Position:

chr14-23425760-C-T

Variant summary

Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.2221G>A(p.Gly741Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G741A) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

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 23 ACMG points.

PS1

Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM1

In a helix (size 9) in uniprot entity MYH7_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000257.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23425759-C-G is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 14-23425760-C-T is Pathogenic according to our data. Variant chr14-23425760-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23425760-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2221G>A	p.Gly741Arg	missense_variant	20/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1 linkuse as main transcript	c.2221G>A	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>A	p.Gly741Arg	missense_variant	20/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000489

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 15, 2014	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. p.Gly741Arg in the MYH7 gene. This variant has been seen in at least 9 cases of HCM. Fananapazir (1993) reported the variant in two unrelated families with HCM; the variant co-segregated with HCM in three affected members of one family and two affected members of the other family. Song et al (2005) observed the variant arising de novo in an individual with HCM. Richard et al (2003) reported the variant in one individual with HCM. Millat et al (2010) reported the identification of this variant in a cohort of individuals studied using high resolution melting to identify variants (this case may be redundant with the Richards et al case as both came from French cohorts). Keller et al (2005) reported the variant in a woman with HCM in their Swiss cohort. Kaski et al (2009) observed the variant in two unrelated children with HCM in a British cohort. We have also observed this variant in another patient with HCM in our clinic. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. Mutation Taster predicts this 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.Gly741Ala (primary data unavailable), p.Gly741Trp (we consider this variant likely disease causing). 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 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 ~6,720 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 ~6,500 Caucasian and African American individuals (as of 9/20/13). There is also no variation at codon 741 listed in dbSNP or 1000 genomes (as of 9/20/13). The variant was not observed in the following published control samples: 120 general population individuals studied by Song et al (2005) (likely Chinese ancestry), 100 healthy adults reported by Richard et al (2003). No further control data was provided by GeneDx or the other authors cited above. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2021	Reported in several other individuals with HCM; however, the nucleotide change was not specified (Malinchik et al., 1997; Van Driest et al., 2004; Kaski et al., 2009; Theis et al., 2009; Kindel et al., 2012; Marsiglia et al., 2013; Miller et al., 2013; Berge et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (ClinVar Variant ID#42890; ClinVar); This variant is associated with the following publications: (PMID: 15358028, 7731997, 22555271, 21216834, 9742053, 20031618, 19808356, 12707239, 25935763, 24093860, 9140824, 8483915, 15563892, 26743238, 28246639, 27247418, 27532257, 29101517, 24111713, 29343710, 23054336, 24704860) -

Hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 22, 2014	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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 present in population databases (rs121913632, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 8483915, 12707239, 20800588, 24111713, 25935763). ClinVar contains an entry for this variant (Variation ID: 42890). 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, 22112859, 26914223). 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. -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 07, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

The p.G741R pathogenic mutation (also known as c.2221G>A), located in coding exon 18 of the MYH7 gene, results from a G to A substitution at nucleotide position 2221. The glycine at codon 741 is replaced by arginine, an amino acid with 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, and a different nucleotide substitution resulting in the same amino acid change (c.2221G>C), were reported to segregate with disease in families with hypertrophic cardiomyopathy (HCM) (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, Circulation 2003 May; 107(17):2227-32; Van Driest SL, J. Am. Coll. Cardiol. 2004 Aug; 44(3):602-10.; Song L, Clin. Chim. Acta 2005 Jan; 351(1-2):209-16; Kindel SJ, J. Card. Fail. 2012 May; 18(5):396-403; Marsiglia JD, Am. Heart J. 2013 Oct; 166(4):775-82; Berge KE, Clin. Genet. 2014 Oct; 86(4):355-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

MYH7-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2022

The MYH7 c.2221G>A variant is predicted to result in the amino acid substitution p.Gly741Arg. This variant was reported in numerous individuals with hypertrophic cardiomyopathy (Fananapazir et al. 1993. PubMed ID: 8483915; Table S1, Captur et al. 2014. PubMed ID: 24704860; Table S1A, Walsh et al. 2017. PubMed ID: 27532257; Filatova et al. 2021. PubMed ID: 34598319). Functional studies in patient-derived muscle fibers showed that the p.Gly741Arg substitution could alter the contractile properties of the mutant protein (Lankford and Fananapazir. 1995. PubMed ID: 7883988). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23894969-C-T). Other different nucleotide substitutions affecting the same amino acid (p.Gly741Trp and p.Gly741Ala) have been reported in individuals with hypertrophic cardiomyopathy (Arai et al. 1995. PubMed ID: 8533830; Van Driest et al. 2004. PubMed ID: 15358028). The c.2221G>A (p.Gly741Arg) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.97

Vest4

0.95

MutPred

0.78

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

MVP

0.99

MPC

2.3

ClinPred

0.98

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.

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