14-23428992-A-T

Variant names:

• chr14-23428992-A-T
• NM_000257.4:c.1370T>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000257.4(MYH7):​c.1370T>A​(p.Ile457Lys) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I457T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.07

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23428992-A-G is described in Lovd as [Pathogenic].
• 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, 0.972
• PP5: Variant 14-23428992-A-T is Pathogenic according to our data. Variant chr14-23428992-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3062303.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.1370T>A	p.Ile457Lys	missense_variant	Exon 14 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.1370T>A	p.Ile457Lys	missense_variant	Exon 13 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.1370T>A	p.Ile457Lys	missense_variant	Exon 14 of 40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:1

-

Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A previously undescribed nucleotide variant creates a missense p.Ile457Lys in the MYH7 gene. The variant was observed in heterozygous state in an individual affected with congenital heart defect including Ebstein anomaly. Heterozygous variants are reported in patients with Cardiomyopathy, dilated, 1S, 613426, Cardiomyopathy, hypertrophic, 1, 192600, Congenital myopathy 7A, myosin storage, autosomal dominant, 608358, Left ventricular noncompaction 5, 613426. Oher missense variants were previously reported in patients with Ebstein anomaly [Postma et al., 2011, PMID: 21127202]. Different missense variants in the same position were reported in patients with hypertrophic cardiomyopathy: p.Ile457Arg [Zhang et al., 2021, PMID: 34330286], p.Ile457Thr [Waldmülleret al., 2011, PMID: 21750094; Fokstuen et al., 2011, PMID: 21239446; Murphy et al., 2016, PMID: 26914223]. The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.79		Gain of catalytic residue at D461 (P = 2e-04);
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.97
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-23898201;