14-23425413-G-C

Variant names:

• chr14-23425413-G-C
• rs121913643
• NM_000257.4:c.2292C>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000257.4(MYH7):​c.2292C>G​(p.Phe764Leu) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.95

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 11 ACMG points.

• PM1: In a region_of_interest Actin-binding (size 14) in uniprot entity MYH7_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.97
• PP5: Variant 14-23425413-G-C is Pathogenic according to our data. Variant chr14-23425413-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14109.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-23425413-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2292C>G	p.Phe764Leu	missense_variant	Exon 21 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2292C>G	p.Phe764Leu	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.2292C>G	p.Phe764Leu	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1S Pathogenic:1

Dec 07, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hypertrophic cardiomyopathy Pathogenic:1

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 764 of the MYH7 protein (p.Phe764Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 11106718; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14109). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 16983074, 17351073, 23313350, 30674652). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.83
Sift	Benign	0.030	D
Sift4G	Uncertain	0.023	D
Polyphen		0.054	B
Vest4		0.97
MutPred		0.81		Gain of catalytic residue at A767 (P = 0.0059);
MVP		0.96
MPC		2.3
ClinPred		0.93	D
GERP RS		2.8
Varity_R		0.72
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: rs121913643; hg19: chr14-23894622;