14-23427597-C-T

Position:

• chr14-23427597-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000257.4(MYH7):​c.1876G>A​(p.Gly626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.98

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.1876G>A	p.Gly626Arg	missense_variant	16/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1876G>A	p.Gly626Arg	missense_variant	15/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1876G>A	p.Gly626Arg	missense_variant	16/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Aug 05, 2011

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Gly626Arg (G626R; c.1876 G>A) in the MYH7 gene This variant appears to be completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism according to searches of PubMed and Google. This is a non-conservative amino acid change from a nonpolar glycine to a positively-charged, basic arginine with a much bigger sidechain. It has a Grantham score of 125. The glycine at codon 626 is highly conserved across 35/37 vertebrate species examined (it is an alanine in microbat and a serine in stickleback). Ambry reports that in silico analysis with PolyPhen-2 (humVAR) predicts the variant to be “benign” with a score of 0.419; SIFT predicts it to be “deleterious” with a score of 0.040. In total this specific variant has not been seen in ~7500 published controls and individuals from publicly available population datasets, including ~2446 individuals ethnicity-matched to our African-American patient. It is not present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). It is not present in dbSNP or in 1000 genomes. (1000 genomes phase 1 is made up of 1092 individuals of various races, 246 of them with African or African-American ancestry). -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 08, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 626 of the MYH7 protein (p.Gly626Arg). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be tolerated (PMID: 21310275). ClinVar contains an entry for this variant (Variation ID: 235027). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2012

There is insufficient or conflicting evidence for classification of this alteration. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
CardioboostCm	Uncertain	0.30
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.39
Sift	Benign	0.051	T
Sift4G	Uncertain	0.024	D
Polyphen		0.16	B
Vest4		0.46
MutPred		0.45		Gain of catalytic residue at Y624 (P = 0.0201);
MVP		0.91
MPC		1.2
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.28
gMVP		0.67

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: rs876661370; hg19: chr14-23896806; COSMIC: COSV105273516;