rs397516259

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000257.4(MYH7):c.610C>T(p.Arg204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,106 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 Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MYH7
NM_000257.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:5

Conservation

PhyloP100: 1.98

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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, 10 uncertain in NM_000257.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-23431789-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43095.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=8, Likely_pathogenic=4}.

PP2

Missense variant where missense usually causes diseases, MYH7

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4 linkuse as main transcript	c.610C>T	p.Arg204Cys	missense_variant	7/40	ENST00000355349.4
MYH7	NM_001407004.1 linkuse as main transcript	c.610C>T	p.Arg204Cys	missense_variant	6/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4 linkuse as main transcript	c.610C>T	p.Arg204Cys	missense_variant	7/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000199

AC:

AN:

251496

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Apr 21, 2021	The NM_000257.4(MYH7):c.610C>T (p.Arg204Cys) variant has been reported in at least 3 individuals with HCM (PS4_Supporting; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.; OMGL pers. comm.) and in 1 infant with LVH/RVH and other complex heart disease (GeneDx pers. comm.). This variant was identified in 0.0026% (FAF 95% CI; 3/30616) South Asian chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PM1. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 29, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the MYH7 protein (p.Arg204Cys). This variant is present in population databases (rs397516259, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 36264615). ClinVar contains an entry for this variant (Variation ID: 181315). 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.Arg204 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12707239, 23816408, 24111713, 24865491, 27247418, 27532257, 27841901). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 04, 2023

This missense variant replaces arginine with cysteine at codon 204 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction suggests that this variant may have 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 at least one individual affected with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 33495597). This variant has been identified in 6/282876 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg204His, is known to be disease-causing (Clinvar variation ID: 43095), indicating that arginine at this position is important for MYH7 protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with cardiomyopathy in published literature, but familial segregation information and additional clinical information were not included (Homburger et al., 2016; Walsh et al., 2017); This variant is associated with the following publications: (PMID: 24865491, 27532257, 27247418, 28606303, 29687901, 27841901, 24111713, 23816408, 12707239, 29300372) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The p.R204C variant (also known as c.610C>T), located in coding exon 5 of the MYH7 gene, results from a C to T substitution at nucleotide position 610. The arginine at codon 204 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 variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts, and in cohorts not selected for the presence of cardiomyopathy; however, clinical details were limited (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; Ganapathy A et al. J Neurol. 2019 Aug;266(8):1919-1926; Yoneda ZT et al. JAMA Cardiol. 2021 Dec;6(12):1371-1379; Park J et al. Hum Mol Genet. 2022 Mar;31(5):827-837). Another alteration at the same codon, p.R204H (c.611G>A), has been reported in association with HCM (Richard P et al. Circulation. 2003;107:2227-32). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.11

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.013

Polyphen

0.99

Vest4

0.81

MVP

0.94

MPC

2.0

ClinPred

0.76

GERP RS

3.1

Varity_R

0.49

gMVP

0.80

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