14-23432713-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):c.428G>A(p.Arg143Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,968 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R143L) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 4.91

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 17 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23432714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164401.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 14-23432713-C-T is Pathogenic according to our data. Variant chr14-23432713-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43006.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23432713-C-T is described in Lovd as [Pathogenic]. Variant chr14-23432713-C-T 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.428G>A	p.Arg143Gln	missense_variant	5/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	4/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.428G>A	p.Arg143Gln	missense_variant	5/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74270

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:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Jun 29, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043006, PS1_S). A different missense change at the same codon (p.Arg143Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000164401, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.803, 3CNET: 0.938, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Mar 10, 2017	The MYH7 Arg143Gln variant has been identified in over 15 HCM probands and has been found to segregate in 2 families (see references; LMM, ClinVar SCV000059551.4). The variant is present as a singleton event in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in a HCM proband, with no family history of sudden cardiac death or disease. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, based on the number of HCM cases identified to harbour the variant, segregation, rarity in the general population and in silico tools supportive of a deleterious effect, we classify MYH7 Arg143Gln as a "likely pathogenic" variant. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 27, 2019	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 16, 2015	The c.428G>A (p.Arg143Gln) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:15563892; PMID:15358028; PMID:21252143; PMID:20075948; PMID:21239446; PMID:22765922; PMID:24093860; Partners LMM ClinVar SCV000059551.5). This variant segregated with disease in 4 affected individuals (PP1; Partners LMM ClinVar SCV000059551.5). This variant has been identified in 1/66732 European chromosomes (PM2; http://exac.broadinstitute.org). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM2; PP1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 03, 2018	The p.Arg143Gln variant in MYH7 has been reported in 15 individuals with HCM (So ng 2005, Van Driest 2004, Wang 2007, Kimura 2010, Gruner 2011, Fokstuen 2011, Ma rsiglia 2013, Meder 2011, Coto 2012, Gomez 2014). It has also been identified by our laboratory in 6 individuals with HCM and segregated with disease in 4 affec ted relatives from 2 families. This variant has been identified in 1/111692 Euro pean chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs397516209) and has been reported in ClinVar (Variation ID : 43006). Computational prediction tools and conservation analysis suggest that the p.Arg143Gln variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Arg143Gln variant is likely pathogenic. ACMG/AMP Criteria applied: PS4, PM2, PP1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 11, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 143 of the MYH7 protein (p.Arg143Gln). This variant is present in population databases (rs397516209, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 15358028, 15563892, 20075948, 21252143, 22765922, 24093860, 26914223, 27247418). ClinVar contains an entry for this variant (Variation ID: 43006). 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 disrupts the p.Arg143 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12820698, 12974739, 22429680, 24510615; Invitae). 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	Mar 20, 2023	Reported in multiple unrelated individuals with HCM (Arai et al., 1995; Kimura et al., 2001; Van Driest et al., 2004; Song et al., 2005; Gruner et al., 2011; Fokstuen et al., 2011; Coto et al., 2012; Curila et al., 2012; Marsiglia et al., 2013; Lopes et al., 2015) and observed in several individuals referred for HCM genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); Located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24093860, 20075948, 8533830, 33673806, 15358028, 15563892, 21511876, 22455086, 25351510, 21252143, 21239446, 27247418, 26914223, 11433818, 27532257, 29300372, 25342278, 18383048, 33487615, 31424582, 23283745, 26656175, 27054166, 28408708, 32894683, 34542152, 35653365, 34726536, 36902152, 34076677, 22765922) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2023	- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 18, 2015	- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 11, 2021

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The p.R143Q variant (also known as c.428G>A), located in coding exon 3 of the MYH7 gene, results from a G to A substitution at nucleotide position 428. The arginine at codon 143 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported multiple times in hypertrophic cardiomyopathy (HCM) cohorts (e.g., Song L et al. Clin. Chim. Acta. 2005;351:209-16; Meder B et al. Circ Cardiovasc Genet. 2011;4:110-22; Coto E et al. J Mol Diagn. 2012;14:518-24; Marsiglia JD et al. Am. Heart J. 2013;166:775-82; Bottillo I et al. Gene. 2016;577:227-35; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

CardioboostCm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.92

MutPred

0.77

Gain of catalytic residue at Y142 (P = 0.0014);

MVP

0.97

MPC

2.2

ClinPred

0.95

GERP RS

3.6

Varity_R

0.57

gMVP

0.92

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