rs397516265

chr14-23431590-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000257.4(MYH7):c.727C>T(p.Arg243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:1
• Conservation: PhyloP100: 3.49

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 10 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 chr14-23431589-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 14126.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=5, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 14-23431590-G-A is Pathogenic according to our data. Variant chr14-23431590-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43101.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=8, Pathogenic=1}. Variant chr14-23431590-G-A is described in Lovd as [Likely_pathogenic]. Variant chr14-23431590-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.727C>T	p.Arg243Cys	missense_variant	8/40	ENST00000355349.4
MYH7	NM_001407004.1	c.727C>T	p.Arg243Cys	missense_variant	7/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.727C>T	p.Arg243Cys	missense_variant	8/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33

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

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74392

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	MYH7: PM1, PM2, PS4:Moderate, PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2023	Not observed at significant frequency in large population cohorts (gnomAD); 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: 20350521, 21799269, 27247418, 27532257, 29121657, 25132132, 32830170, 33705529, 30297972, 35653365, 33487615, 29300372) -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hypertrophic cardiomyopathy Pathogenic:2 Uncertain:1

Likely 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 243 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). 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). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2021	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 243 of the MYH7 protein (p.Arg243Cys). This variant is present in population databases (rs397516265, gnomAD 0.007%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43101). 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.Arg243 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18506004, 20965760, 21551322; 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. -

Cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 14, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 14, 2023	This missense variant replaces arginine with cysteine at codon 243 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. 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). Experimental functional studies using human induced pluripotent stem cells have shown that this variant causes impaired cardiomyocyte relaxation and increased multinucleation (PMID: 33705529). This variant has been reported in at least six individuals affected with hypertrophic cardiomyopathy (PMID: 21799269, 27247418, 27532257, 30297972, 32815737, 32830170). This variant has been identified in 1/31404 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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

Jul 01, 2021

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2024

The p.R243C variant (also known as c.727C>T), located in coding exon 6 of the MYH7 gene, results from a C to T substitution at nucleotide position 727. The arginine at codon 243 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in association with hypertrophic cardiomyopathy (HCM) (Hirota T et al. J Cardiol, 2010 Jul;56:59-65; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). 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). Another alteration at the same codon, p.R243H (c.728G>A), has been identified in multiple probands with left ventricular noncompaction cardiomyopathy (LVNC), dilated cardiomyopathy, and HCM and has been reported to segregate with disease (Klaassen S et al. Circulation, 2008 Jun;117:2893-901; Chang B et al. Mol. Genet. Metab., 2011 Feb;102:200-6; van Waning JI et al. J. Am. Coll. Cardiol., 2018 Feb;71:711-722; Invitae pers. comm.; OMGL pers. comm.). 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. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.85		Gain of catalytic residue at K246 (P = 0.0041);
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.82
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

Other links and lift over

dbSNP: rs397516265; hg19: chr14-23900799; COSMIC: COSV105912886;