14-23424770-G-T

Variant names:

• chr14-23424770-G-T
• rs727503254
• NM_000257.4:c.2678C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS4_Supporting PM1 PM2

This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) variant has been reported in 3 individuals with HCM (PS4_Supporting; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with HCM in 2 relatives from 2 families (GeneDx pers. comm.; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012807/MONDO:0005045/002

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense, splice_region
• Scores: Splicing: ADA: 0.9714
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4
• Conservation: PhyloP100: 9.47
• Publications: 10 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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	Exon 22 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	Exon 21 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	Exon 22 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	Exon 22 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	Exon 21 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Mar 10, 2021

ClinGen Cardiomyopathy Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000257.4(MYH7):c.2678C>A (p.Ala893Glu) variant has been reported in 3 individuals with HCM (PS4_Supporting; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.) and segregated with HCM in 2 relatives from 2 families (GeneDx pers. comm.; LMM pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://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. -

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 893 of the MYH7 protein (p.Ala893Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 31737537; Invitae). ClinVar contains an entry for this variant (Variation ID: 164319). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ala893 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22464770, 23054336, 27532257, 29300372, 29447731, 34935411; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Pathogenic:1

May 03, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jun 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala893Glu variant in MYH7 has been identified by our laboratory in 1 Cauca usian individual with HCM and segregated with disease in 1 affected family membe r. It was absent from large population studies; however, it is listed in dbSNP w ith no frequency data (rs727503254). Alanine (Ala) at position 893 is not conser ved in mammals or evolutionarily distant species and the change to glutamic acid (Glu) was predicted to be benign using a computational tool clinically validate d by our laboratory. This tool's benign prediction is estimated to be correct 89 % of the time (Jordan 2011). This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not sugg est an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala893G lu variant is uncertain. -

Cardiovascular phenotype Uncertain:1

Jun 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A893E variant (also known as c.2678C>A), located in coding exon 20 of the MYH7 gene, results from a C to A substitution at nucleotide position 2678. The alanine at codon 893 is replaced by glutamic acid, an amino acid with 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 was reported in individual(s) with features consistent with MYH7-related cardiomyopathy (Ware SM et al. Am J Hum Genet, 2022 Feb;109:282-298; Harper AR et al. Nat Genet, 2021 Feb;53:135-142; Hirono K et al. J Am Heart Assoc, 2024 Nov;13:e035614; external communication). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.071	T
Polyphen		0.94	P
Vest4		0.59
MutPred		0.38		Gain of solvent accessibility (P = 0.194);
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.88
gMVP		1.0
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.66
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: rs727503254; hg19: chr14-23893979;