14-23424863-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000257.4(MYH7):​c.2585C>G​(p.Ala862Gly) 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

Scores

2
11
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.958
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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;
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.2585C>G p.Ala862Gly missense_variant Exon 22 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.2585C>G p.Ala862Gly missense_variant Exon 21 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.2585C>G p.Ala862Gly missense_variant Exon 22 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthMar 04, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 16, 2018- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 22, 2022Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 29300372) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
CardioboostCm
Uncertain
0.29
BayesDel_addAF
Benign
-0.024
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.92
D
M_CAP
Pathogenic
0.72
D
MetaRNN
Uncertain
0.69
D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-2.0
N
REVEL
Uncertain
0.40
Sift
Benign
0.12
T
Sift4G
Benign
0.33
T
Polyphen
0.20
B
Vest4
0.57
MutPred
0.51
Gain of catalytic residue at L863 (P = 0.0143);
MVP
0.92
MPC
1.3
ClinPred
0.71
D
GERP RS
4.7
Varity_R
0.27
gMVP
0.97

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: rs149576470; hg19: chr14-23894072; API