14-23424046-T-G

Position:

• chr14-23424046-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000257.4(MYH7):​c.2783A>C​(p.Asp928Ala) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D928N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.85

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 120) in uniprot entity MYH7_HUMAN there are 91 pathogenic changes around while only 3 benign (97%) 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 chr14-23424047-C-T is described in Lovd as [Pathogenic].
• 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). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. GenCC has associacion of the 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2783A>C	p.Asp928Ala	missense_variant	23/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2783A>C	p.Asp928Ala	missense_variant	22/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2783A>C	p.Asp928Ala	missense_variant	23/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 03, 2013

The Asp928Ala variant in MYH7 has been reported in 1 individual with HCM as well as 3 asymptomatic relatives (Michels 2009) and was not identified in large popu lation studies (http://evs.gs.washington.edu/EVS/). Another variant at this pos ition (Asp928Asn) has been reported in individuals with HCM (Erdman 2003, Gimeno 2009, Perrot 2005), suggesting that a change at this position may not be tolera ted. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) suggest that the Asp928Ala variant may impact the protein, though this information is not predictive enough to determine pathogen icity. Additional information is needed to fully assess the clinical significan ce of the Asp928Ala variant. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2017

The p.D928A variant (also known as c.2783A>C), located in coding exon 21 of the MYH7 gene, results from an A to C substitution at nucleotide position 2783. The aspartic acid at codon 928 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Other alterations affecting this amino acid (p.D928G, p.D928N, and p.D928V) have been reported in individuals with HCM (Erdmann J et al. Clin Genet. 2003 Oct;64(4):339-49; Michels M. Eur. Heart J. 2009 Nov;30(21):2593-8; Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Uncertain	0.51
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.78	P
Vest4		0.67
MutPred		0.57		Gain of catalytic residue at M932 (P = 0);
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.69
gMVP		0.99

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: rs727504558; hg19: chr14-23893255;