14-23425371-G-T

Variant names:

• chr14-23425371-G-T
• rs2069544
• NM_000257.4:c.2334C>A

Variant summary

Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.2334C>A​(p.Asp778Glu) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D778N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.262

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 27 ACMG points.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 265252
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23425372-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 14-23425371-G-T is Pathogenic according to our data. Variant chr14-23425371-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 188615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2334C>A	p.Asp778Glu	missense_variant	Exon 21 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2334C>A	p.Asp778Glu	missense_variant	Exon 20 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2334C>A	p.Asp778Glu	missense_variant	Exon 21 of 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 10, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Dec 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid with glutamic acid at codon 778 of the MYH7 protein (p.Asp778Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy (PMID: 22112859). ClinVar contains an entry for this variant (Variation ID: 188615). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.2334C>G) giving rise to the same protein effect observed here (p.Asp778Glu) has been determined to be pathogenic (PMID: 12566107, 21896538, 12707239, 27247418, 29121657). This suggests that this variant is also likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Oct 14, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D778E pathogenic mutation (also known as c.2334C>A), located in coding exon 19 of the MYH7 gene, results from a C to A substitution at nucleotide position 2334. The aspartic acid at codon 778 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported to segregate with hypertrophic cardiomyopathy (HCM) in one Japanese family (Otsuka H et al. Circ. J. 2012;76:453-61). In addition, a disease-causing mutation resulting in the same amino acid change (c.2443C>G p.D778E) has been detected in several unrelated individuals with hypertrophic cardiomyopathy and has been shown to segregate with hypertrophic cardiomyopathy (HCM) in two of those families (Andersen PS et al. J. Med. Genet. 2001;38:E43; Havndrup O et al. Cardiovasc. Res. 2003;57:347-57; Richard P et al. Circulation. 2003;107:2227-32). The c.2443C>G alteration has also been identified in the homozygous state in two related individuals with HCM who suffered sudden death at a young age (Richard P et al. Circulation. 2003;107:2227-32). Other alterations at the same codon (p.D778V and p.D778G) have also been associated with HCM (Harada H et al. Biochem. Biophys. Res. Commun. 1993;194:791-8; Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:602-10). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	5.6
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.73
MutPred		0.78		Gain of catalytic residue at L773 (P = 0.0738);
MVP		0.91
MPC		2.1
ClinPred		0.99	D
GERP RS		-9.2
Varity_R		0.59
gMVP		0.96

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: rs2069544; hg19: chr14-23894580;