chr14-23428508-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000257.4(MYH7):​c.1570A>G​(p.Ile524Val) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

8
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

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, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.1570A>G p.Ile524Val missense_variant Exon 15 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.1570A>G p.Ile524Val missense_variant Exon 14 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.1570A>G p.Ile524Val missense_variant Exon 15 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 08, 2015Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile524Val variant in MYH7 has been identified by our laboratory in 1 Caucasian infant wit h DCM. It was absent from large population studies. Isoleucine (Ile) at position 524 is highly conserved in evolution and the change to valine (Val) was predict ed to be pathogenic using a computational tool clinically validated by our labor atory. This tool's pathogenic prediction is estimated to be correct 94% of the t ime (Jordan 2011). In summary, while there is some suspicion for a pathogenic ro le, the clinical significance of the p.Ile524Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.79
T
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Uncertain
2.1
M
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.86
N
REVEL
Pathogenic
0.80
Sift
Benign
0.064
T
Sift4G
Uncertain
0.044
D
Polyphen
0.16
B
Vest4
0.75
MutPred
0.65
Gain of catalytic residue at I524 (P = 0.0018);
MVP
0.83
MPC
1.8
ClinPred
0.92
D
GERP RS
4.6
Varity_R
0.39
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504401; hg19: chr14-23897717; API