rs727504385

Variant names:

• chr14-23415210-T-C
• rs727504385
• NM_000257.4:c.5344A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-23415210-T-C
• chr14-23415210-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.5344A>G​(p.Met1782Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. M1782I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 7.72
• Publications: 3 publications found

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]

ENSG00000258444 (HGNC:):

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879
• PP5: Variant 14-23415210-T-C is Pathogenic according to our data. Variant chr14-23415210-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 177892.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5344A>G	p.Met1782Val	missense_variant	Exon 37 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5344A>G	p.Met1782Val	missense_variant	Exon 36 of 39		NP_001393933.1
MHRT	NR_126491.1	n.-240T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5344A>G	p.Met1782Val	missense_variant	Exon 37 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5344A>G	p.Met1782Val	missense_variant	Exon 37 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5344A>G	p.Met1782Val	missense_variant	Exon 36 of 39			ENSP00000519071.1
ENSG00000258444	ENST00000557368.1	n.-129T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Sep 12, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

p.Met1782Val (c.5344A>G) in the MYH7 gene (NM_000257.3) We have seen this variant in one Caucasian individual with HCM. Given the location, absence from population databases and presence in a small number of affected patients (but without segregation or functional data), we consider this variant a variant of uncertain significance, probably disease causing and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 3 unrelated cases of hypertrophic cardiomyopathy (HCM) (not including this patient's family). There is weak case data. A 2015 study by Alfares et al assessed 2912 unrelated nonsyndromic HCM probands and 1209 family members referred between 2004 and 2013. Testing of up to 51 genes associated with HCM was conducted. The variant of interest was identified in a single proband and classified as “likely pathogenic,” though segregation information is not available. Per the Invitae report: “This variant has been observed in two unrelated patients with obstructive HCM who had positive family histories (Invitae database).” The variant is not in the head (the head is enriched for pathogenic variation). In addition, the variant is not in any of the regions we found enriched for pathogenic variation when comparing HCM patients to ExAC (Homburger et al 2016). There is no variation at codon 1782 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 4/12/16). Median coverage at that site is 100. -

Oct 19, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in ClinVar (ClinVar Variant ID# 177892; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); 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: 26914223, 27247418, 27532257, 25611685, 28606303, 30297972) -

Hypertrophic cardiomyopathy Pathogenic:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1782 of the MYH7 protein (p.Met1782Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685, 26914223, 27247418, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 177892). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Nov 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype Uncertain:1

Feb 21, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M1782V variant (also known as c.5344A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide position 5344. The methionine at codon 1782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy; however, clinical information was limited in most cases, and segregation information was not available (Alfares AA et al. Genet. Med., 2015 Nov;17:880-8; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly 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	Pathogenic	0.81
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.72
MutPred		0.37		Gain of methylation at K1783 (P = 0.0319);
MVP		0.91
MPC		1.5
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.71
gMVP		0.88
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504385; hg19: chr14-23884419;