chr14-23424770-G-T

Position:

• chr14-23424770-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PS4_Supporting

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:3
• Conservation: PhyloP100: 9.47

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.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	22/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	21/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2678C>A	p.Ala893Glu	missense_variant, splice_region_variant	22/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Mar 10, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 31737537; Invitae). This variant is not present in population databases (gnomAD no frequency). 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). ClinVar contains an entry for this variant (Variation ID: 164319). 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. 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 03, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 10, 2015

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. -

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
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503254; hg19: chr14-23893979;