rs121913618
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002470.4(MYH3):c.2014C>T(p.Arg672Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R672H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
MYH3
NM_002470.4 missense
NM_002470.4 missense
Scores
13
2
1
Clinical Significance
Conservation
PhyloP100: 6.75
Genes affected
MYH3 (HGNC:7573): (myosin heavy chain 3) Myosin is a major contractile protein which converts chemical energy into mechanical energy through the hydrolysis of ATP. Myosin is a hexameric protein composed of a pair of myosin heavy chains (MYH) and two pairs of nonidentical light chains. This gene is a member of the MYH family and encodes a protein with an IQ domain and a myosin head-like domain. Mutations in this gene have been associated with two congenital contracture (arthrogryposis) syndromes, Freeman-Sheldon syndrome and Sheldon-Hall syndrome. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
?
In a region_of_interest Actin-binding (size 22) in uniprot entity MYH3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002470.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-10641317-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, MYH3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
?
Variant 17-10641318-G-A is Pathogenic according to our data. Variant chr17-10641318-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-10641318-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYH3 | NM_002470.4 | c.2014C>T | p.Arg672Cys | missense_variant | 18/41 | ENST00000583535.6 | |
MYH3 | XM_011523870.4 | c.2014C>T | p.Arg672Cys | missense_variant | 18/41 | ||
MYH3 | XM_011523871.3 | c.2014C>T | p.Arg672Cys | missense_variant | 18/41 | ||
MYH3 | XM_047436127.1 | c.2014C>T | p.Arg672Cys | missense_variant | 20/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYH3 | ENST00000583535.6 | c.2014C>T | p.Arg672Cys | missense_variant | 18/41 | 5 | NM_002470.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 13, 2021 | This sequence change replaces arginine with cysteine at codon 672 of the MYH3 protein (p.Arg672Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change alters MYH3 kinetic properties in skeletal muscle cells (PMID: 25740846, 26945064). This variant has been reported in several individuals affected with Freeman-Sheldon syndrome, including some in which the variant was found to be de novo (PMID: 16642020, 20924721, 25256237, 25740846). ClinVar contains an entry for this variant (Variation ID: 14139). This variant is not present in population databases (ExAC no frequency). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2022 | Published functional studies in Drosophila demonstrate that this variant reduces ATPase activity and causes abnormal muscle structure and function (Rao et al., 2019; Das et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32714615, 28584669, 25740846, 30826400, 26180627, 31966463, 26494722, 25957469, 31085342, 29625835, 31746383, 28205584, 20924721, 30379605, 26275891, 16642020) - |
Freeman-Sheldon syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2006 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0762);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at