rs587782962

Positions:

chr14-23422267-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_StrongPM2PP3PS4

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected individuals with HCM in 9 families (PP1_Moderate; Kärkkäinen 2004 PMID:15556047; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.040% (FAF 95% CI; 16/25124) of Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other populations and is an established Finnish founder variant. 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013417/MONDO:0005045/002

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 7.76

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 11 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.3158G>A	p.Arg1053Gln	missense_variant	25/40	ENST00000355349.4	NP_000248.2	P12883
MYH7	NM_001407004.1 linkuse as main transcript	c.3158G>A	p.Arg1053Gln	missense_variant	24/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.3158G>A	p.Arg1053Gln	missense_variant	25/40	1	NM_000257.4	ENSP00000347507.3		P12883

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251478

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135916

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:

0.000739

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000150

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727216

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:

0.0000116

Gnomad4 FIN exome

AF:

0.000356

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000741

AC:

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	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	Aug 06, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Nov 30, 2021	The NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln) variant in MYH7 has been reported in >35 individuals with hypertrophic cardiomyopathy (HCM), a large proportion of which are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant segregated with disease in >15 affected individuals with HCM in 9 families (PP1_Moderate; Kärkkäinen 2004 PMID:15556047; GeneDx pers. comm.; OMGL pers. comm.). This variant was identified in 0.040% (FAF 95% CI; 16/25124) of Finnish chromosomes in gnomAD v2.1.1 (http://gnomad.broadinstitute.org), but was absent from other populations and is an established Finnish founder variant. 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PP1_Strong; PM2; PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1053 of the MYH7 protein (p.Arg1053Gln). This variant is present in population databases (rs587782962, gnomAD 0.07%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 15556047, 20624503, 24888384, 27247418, 27460395, 27532257). ClinVar contains an entry for this variant (Variation ID: 155814). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	This missense variant replaces arginine with glutamine at codon 1053 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction suggests that this variant may have a 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 more than 30 individuals affected with hypertrophic cardiomyopathy (PMID: 15556047, 20624503, 24888384, 27532257, 29300372, 30775854, 31737537, 33673806, 34615813). It has been described as a founder variant in the Finnish population (PMID: 24888384). It has been shown that this variant segregates with disease in 6 affected individuals in one family (PMID: 15556047). This variant has been identified in 17/282864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2014	The Arg1053Gln variant in MYH7 has been reported in 1 individual with a dilated left ventrical and impaired systolic function, and was present in 5 additional a ffected family members with clinical features of septal HCM (Karkkainen 2004). I n addition, it has been identified by our laboratory in 1 individual with HCM an d family history of SCD. The variant was absent from large population studies. Arganine (Arg) at position 1053 is highly conserved in evolution and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) bas ed upon segregation studies and absence from controls. -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2023	Reported in Finnish patients with HCM and described as the third most common mutation encountered in Finnish patients with HCM (Jskelinen et al., 2014); 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: 15556047, 30775854, 27247418, 27532257, 29300372, 21310275, 33673806, 31737537, 24888384, 20624503, 35626289, 35753512) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 28, 2022

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 20, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The p.R1053Q pathogenic mutation (also known as c.3158G>A), located in coding exon 23 of the MYH7 gene, results from a G to A substitution at nucleotide position 3158. The arginine at codon 1053 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), including segregating with disease in one family (Kärkkäinen S, Eur. J. Heart Fail. 2004 Dec; 6(7):861-8; Millat G et al. Eur J Med Genet Jul;53:261-7; Walsh R et al. Genet Med, 2017 02;19:192-203; Kelly MA et al. Genet Med, 2018 03;20:351-359; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298; Costain G et al. JAMA Netw Open, 2020 09;3:e2018109; Yoshinaga M et al. Circ J, 2021 12;86:118-127; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This alteration has also been described as a founder mutation in a Finnish HCM cohort, accounting for approximately 5-8% of MYH7 variants detected (Jääskeläinen P et al. Ann. Med., 2014 Sep;46:424-9; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

0.81

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.96

MutPred

0.66

Loss of MoRF binding (P = 0.0283);

MVP

0.99

MPC

1.2

ClinPred

0.97

GERP RS

4.6

Varity_R

0.45

gMVP

0.78

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