rs2754158

chr14-23424876-G-Achr14-23424876-G-Cchr14-23424876-G-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.2572C>T(p.Arg858Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,614,080 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. R858G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 1.20

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 0 benign, 13 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23424875-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520277.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, 0.972

PP5

Variant 14-23424876-G-A is Pathogenic according to our data. Variant chr14-23424876-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23424876-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.2572C>T	p.Arg858Cys	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.2572C>T	p.Arg858Cys	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.2572C>T	p.Arg858Cys	missense_variant	22/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251442

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as likely pathogenic (ClinVar Variant ID# 164324; ClinVar); 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: 24111713, 25086479, 15358028, 29169752, 34542152, 25125180, 26187847, 25937619, 24093860, 27532257, 22958901, 27247418, 19149795, 16938236, 28498465, 24621997, 28971120, 20975235, 31513939, 31589614, 32894683, 33087929, 35653365, 29300372) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Sep 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 05, 2021	- -

Hypertrophic cardiomyopathy

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces arginine with cysteine at codon 858 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16938236, 19149795, 20975235, 24793961, 25086479, 25937619, 27247418, 27532257, 28498465, 28971120, 31513939, 33495597) and has been shown to segregate with disease in a family study (PMID: 25086479). A different missense variant occurring at the same codon, p.Arg858His (ClinVar variation ID: 177696), is known to be pathogenic, indicating that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251442 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	Apr 02, 2024	The p.Arg858Cys variant in MYH7 has been reported in at least 15 heterozygous individuals with hypertrophic cardiomyopathy (HCM; Ven Driest 2004 PMID: 15358028, Mora 2006 PMID: 16938236, Uchiyama 2009 PMID: 19149795, Funada 2010 PMID: 20975235, Bick 2012 PMID: 22958901, Marsiglia 2013 PMID: 24093860, Berge 2014 PMID: 24111713, Bos 2014 PMID: 24793961, Li 2015 PMID: 26187847, Chiou 2015 PMID: 25086479, Walsh 2017 PMID: 27532257, Robyns 2020 PMID: 31513939) and reportedly occurred as a de novo variant in 1 individual with HCM (Zhao 2017 PMID: 28498465). It has also segregated with disease in at least 6 affected relatives from 1 family (Chiou 2015 PMID: 25086479). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 164324) and in 0.003% (2/60008) of Admixed American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016 PMID: 27532257). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Moderate, PM1, PM2_supporting, PM6_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 858 of the MYH7 protein (p.Arg858Cys). This variant is present in population databases (rs2754158, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15358028, 24093860, 28498465). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 164324). 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. -

Hypertrophic cardiomyopathy 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2023	- -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2023	This missense variant replaces arginine with cysteine at codon 858 in the neck and hinge (S2) domain of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16938236, 19149795, 20975235, 24793961, 25086479, 25937619, 27247418, 27532257, 28498465, 28971120, 31513939, 33495597) and has been shown to segregate with disease in a family study (PMID: 25086479). A different missense variant occurring at the same codon, p.Arg858His (ClinVar variation ID: 177696), is known to be pathogenic, indicating that arginine at this position is important for MYH7 protein function. This variant has been identified in 3/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Dilated cardiomyopathy 1S;C3495498:Hypertrophic cardiomyopathy 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 14, 2023

The c.2572C>T p.(Arg858Cys) variant in MYH7 has previously been reported in multiple individuals with hypertrophic cardiomyopathy in heterozygous state (PMID: 15358028, 16938236, 19149795, 24093860, 20975235, 28498465, 34542152, 35653365), and has been deposited in ClinVar database as Pathogenic/Likely Pathogenic by multiple independent laboratories [ClinVar ID: 164324]. The c.2572C>T variant is observed in 14 alleles (~0.0023% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.2572C>T variant in MYH7 is located in exon 22 of this 40-exon gene and predicted to replace a moderately conserved arginine amino acid with cysteine at position 858 in the coiled coil domain (839-1935aa; Uniprot ID: P12883) of the encoded protein. In silico predictions are favor of damaging effect for the p.(Arg858Cys) variant [REVEL = 0.631]; however, there are no functional studies to support or refute these predictions. Another missense substitution affecting the same protein residue c.2573G>C, p.(Arg858Pro) has been reported in the literature [PMID: 27247418, 27532257] and in ClinVar [ClinVar ID: 520277] in individuals with hypertrophic cardiomyopathy. Based on available evidence this c.2572C>T, p.(Arg858Cys) variant identified in MYH7 is classified as Likely Pathogenic -

Myopathy, myosin storage, autosomal recessive

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

Myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Oct 05, 2015

- -

Dilated cardiomyopathy 1S

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

MYH7-related skeletal myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

Myosin storage myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

Congenital myopathy with fiber type disproportion

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Likely pathogenic. -

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

Apr 14, 2022

- -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The p.R858C variant (also known as c.2572C>T), located in coding exon 20 of the MYH7 gene, results from a C to T substitution at nucleotide position 2572. The arginine at codon 858 is replaced by cysteine, 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 alteration has been reported in individuals with hypertrophic cardiomyopathy (Funada A et al. Circ. J., 2010 Nov;74:2674-80; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Zhao Y et al. Int. J. Mol. Med., 2017 Jul;40:121-129). This alteration was also described to segregate with the disease in one family (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Benign

0.15

CardioboostCm

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.18

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Benign

0.15

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.45

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.66

MutPred

0.84

Gain of catalytic residue at L859 (P = 0.0018);

MVP

0.91

MPC

2.3

ClinPred

0.86

GERP RS

3.8

Varity_R

0.32

gMVP

0.95

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