14-23429005-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000257.4(MYH7):​c.1357C>A​(p.Arg453Ser) 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 missense

Scores

10
6
4

Clinical Significance

Pathogenic reviewed by expert panel P:2U:1

Conservation

PhyloP100: 1.75
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 Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr14-23429005-G-A 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, 0.973
PP5
Variant 14-23429005-G-T is Pathogenic according to our data. Variant chr14-23429005-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 14129.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429005-G-T is described in Lovd as [Pathogenic]. Variant chr14-23429005-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYH7NM_000257.4 linkc.1357C>A p.Arg453Ser missense_variant Exon 14 of 40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkc.1357C>A p.Arg453Ser missense_variant Exon 13 of 39 NP_001393933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkc.1357C>A p.Arg453Ser missense_variant Exon 14 of 40 1 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1
Jun 16, 2021
ClinGen Cardiomyopathy Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.1357C>A (p.Arg453Ser) variant in MYH7 has been identified in 3 individuals with HCM, including 1 individual with early onset HCM (<20 yo; PS4_Supporting; Frazier 2008 PMID:18175163; Walsh 2017 PMID:27532257; Centenary Institute Sydney pers. comm.; LMM pers. comm.) and segregated with disease in 9 affected relatives with HCM from 2 families (PP1_Strong; Centenary Institute Sydney pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; http:/gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Two different missense variants that have been classified as pathogenic by this expert panel have been previously identified at this codon, which indicate that this residue may be critical to the function of the protein (PM5; c.1358G>T, p.Arg453His - Variation ID 42838 and c.1357C>T, p.Arg453Cys - Variation ID 14089). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257); however, because the other pathogenic variants at this codon were used to establish this enrichment, PM1 cannot be used in combination with PM5. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Strong; PM2; PP3; PM5. -

Hypertrophic cardiomyopathy 1 Pathogenic:1
Jul 01, 2008
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Uncertain:1
Mar 07, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Benign
0.61
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.4
D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.093
T
Polyphen
1.0
D
Vest4
0.84
MutPred
0.81
Gain of catalytic residue at Q454 (P = 0.0057);
MVP
0.96
MPC
2.2
ClinPred
0.99
D
GERP RS
4.2
Varity_R
0.92
gMVP
0.98

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: rs121913625; hg19: chr14-23898214; API