chr14-23428601-T-C

Position:

• chr14-23428601-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PS4_Moderate PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1477A>G (p.Met493Val) variant in MYH7 has been reported in at least 8 individuals with HCM (PS4_Moderate; Meyer 2013 PMID:23816408; Marsiglia 2013 PMID:24093860; Walsh 2017 PMID:27532257; LMM pers. comm.; Ambry pers. comm.; GeneDx pers. comm.). This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. 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; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PM2_Supporting; PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA010805/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.78

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 Uncertain_significance. Variant got 5 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.1477A>G	p.Met493Val	missense_variant	15/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1477A>G	p.Met493Val	missense_variant	14/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1477A>G	p.Met493Val	missense_variant	15/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (PMID: 32492895, 37652022, 36136372, 23816408, 27532257); 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: 24093860, 28606303, 23816408, 27532257, 32492895, 17599605, 37652022, 29300372, 36136372) -

Hypertrophic cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 26, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met493 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been observed in individuals with MYH7-related conditions (PMID: 24093860, 28615295), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 181349). This missense change has been observed in individuals with autosomal dominant MYH7-related cardiomyopathy (PMID: 17599605, 23816408, 27532257, 32492895; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 493 of the MYH7 protein (p.Met493Val). -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 09, 2023

Variant summary: MYH7 c.1477A>G (p.Met493Val) results in a conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251488 control chromosomes (gnomAD). c.1477A>G has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Meyer_2013, Walsh_2017, Kim)2020, Nafissi_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32492895, 23816408, 36136372, 27532257). Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance and four as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2022

The p.M493V variant (also known as c.1477A>G), located in coding exon 13 of the MYH7 gene, results from an A to G substitution at nucleotide position 1477. The methionine at codon 493 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in individuals reported to have hypertrophic cardiomyopathy (HCM) (Meyer T et al. Gene. 2013 Sep;527:416-20; Walsh R et al. Genet Med. 2017;19:192-203). In addition, other alterations at the same codon (p.M493I and p.M493L) have also been reported in association with cardiomyopathy (Marsiglia JD et al. Am Heart J. 2013;(1):416-20; Homburger Proc Natl Acad Sci USA. 2016 06;113(24):6701-6; Walsh R et al. Genet Med. 2017;19:192-203; Kubo T et al. Am Coll Cardiol. 2007;49(25):2419-26). Furthermore, internal structural analysis indicates this alteration is located in the myosin head region, and would be expected to disrupt the stroke motion of the protein (Gourinath S et al. Structure. 2003;11(12):1621-7; Risal D et al. Proc Natl Acad Sci USA. 2004;101(24):8930-5). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.076	B
Vest4		0.96
MutPred		0.76		Gain of catalytic residue at E497 (P = 0.0173);
MVP		0.90
MPC		1.4
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.98

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: rs730880875; hg19: chr14-23897810;