14-23425814-G-C

Position:

• chr14-23425814-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_Strong PM1 PM5 PM2 PP3 PS4

This summary comes from the ClinGen Evidence Repository: The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, PMID:30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:11113006). This variant was absent from large population studies (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>T p.Arg723Cys - ClinVar Variation ID 14095). 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 (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011843/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 2.03

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 15 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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	c.2167C>G	p.Arg723Gly	missense_variant	20/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2167C>G	p.Arg723Gly	missense_variant	19/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2167C>G	p.Arg723Gly	missense_variant	20/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 30, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 18, 2020	PP1_Strong, PS4, PS3, PM1, PM2, PM5, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2017	The R723G pathogenic variant in the MYH7 gene has been reported in many individuals with HCM (Enjuto et al., 2000; Yang et al., 2006; Gacia-Castro et al., 2009; Tripathi et al., 2011; Zheng et al., 2010; Coto et al., 2012; Marsiglia et al., 2013; Gomez et al., 2014). In multiple unrelated cases, the variant segregated with disease throughout large multi-generational families (Enjuto et al., 2000; Yang et al., 2010; Zheng et al., 2010). Allelic expression studies on skeletal and myocardium tissue from one family showed a larger R237G load compared to the wild-type allele, and load seemed to be correlated with disease severity (Enjuto et al., 2000; Tripathi et al., 2011). Additionally, the R723G variant has been reported as a likely pathogenic or pathogenic variant in multiple individuals with HCM who were referred for genetic testing at GeneDx and other clinical laboratories (ClinVar SCVSCV000256127.1, SCV000284260.1, SCV000059422.4; Landrum et al., 2016). Two variants at the same residue (R723C, R723H) are also reported as likely pathogenic or pathogenic.The R723G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R723G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, analysis of skeletal muscle and cardiomyocytes from individuals harboring the R723G variant showed myofibrillar deficiency and disarray with reduced calcium sensitivity and increased stiffness of the myosin-head, resulting in decreased force generation for cardiomyocytes, in particular (Seebohm et al., 2009; Kraft et al., 2013; Brenner et al., 2014). It is suggested that these effects activate stretch-sensitive signaling and, in turn, results in cardiac remodeling, the hallmark of HCM. -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 11, 2017	The p.Arg723Gly variant in MYH7 has been reported in the literature in at least four families with HCM, progressive CHF, and sudden cardiac death, segregated wi th disease in >20 affected relatives, and was absent from 400 control chromosome s (Enjuto 2000, Yang 2006). This variant is also absent from large population st udies. This variant is reported in ClinVar (Variant ID 42885) and classified as pathogenic by an expert panel. This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathog enic prediction is estimated to be correct 94% of the time (Jordan 2011). Of not e, this variant lies in the head region of the protein. Missense variants in thi s region have been reported and statistically indicated to be more likely to cau se disease (Walsh 2016). In summary, the p.Arg723Gly variant meets our criteria to be classified as pathogenic based upon segregation studies, absence in contro ls, and computational assessment. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2167C>G (p.Arg723Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PS4; PMID:11113006; PMID:19150014; PMID:17097032; Partners LMM ClinVar SCV000059422.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >20 affected individuals (PP1_Strong; PMID:11113006). This variant was absent from large population studies (PM2; http://exac.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 disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2167C>T p.Arg723Cys - ClinVar Variation ID 14095). 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 (PMID:29300372): PS4; PP1_ Strong; PM1; PM2; PM5; PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 723 of the MYH7 protein (p.Arg723Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 11113006, 17097032, 19150014, 20865685, 24093860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42885). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19651039, 23318932, 25346696). This variant disrupts the p.Arg723 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1430197, 9829907, 12707239, 21835320). 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. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Jun 28, 2016

- -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.7	L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.10	T
Polyphen		0.97	D
Vest4		0.95
MutPred		0.83		Gain of catalytic residue at R719 (P = 0);
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.53
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913630; hg19: chr14-23895023;