rs878854030
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000530.8(MPZ):c.368_369delinsCT(p.Gly123Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G123C) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 29)
Consequence
MPZ
NM_000530.8 missense
NM_000530.8 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.15
Genes affected
MPZ (HGNC:7225): (myelin protein zero) This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major structural protein of the peripheral myelin sheath. The encoded protein contains a large hydrophobic extracellular domain and a smaller basic intracellular domain, which are essential for the formation and stabilization of the multilamellar structure of the compact myelin. Mutations in this gene are associated with autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B) and other polyneuropathies, such as Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN). A recent study showed that two isoforms are produced from the same mRNA by use of alternative in-frame translation termination codons via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000530.8
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr1-161306788-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449537.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPZ | NM_000530.8 | c.368_369delinsCT | p.Gly123Ala | missense_variant | 3/6 | ENST00000533357.5 | |
MPZ | NM_001315491.2 | c.368_369delinsCT | p.Gly123Ala | missense_variant | 3/6 | ||
MPZ | XM_017001321.3 | c.398_399delinsCT | p.Gly133Ala | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPZ | ENST00000533357.5 | c.368_369delinsCT | p.Gly123Ala | missense_variant | 3/6 | 1 | NM_000530.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 29
GnomAD4 genome
?
Cov.:
29
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2016 | This sequence change deletes 2 nucleotides and inserts 2 different nucleotides in exon 3 of the MPZ mRNA (c.368_369delGCinsCT). This results in a substitution of glycine at codon 123 with alanine. In summary, this is a novel missense change and although multiple missense variants have been reported at this codon in individuals with CMT, in the absence of additional functional data and/or segregation data, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (PolyPhen-2, Align-GVGD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MPZ-related disease. However, multiple other missense variants have been reported at codon 123 in individuals with Charcot-Marie-Tooth (CMT) disease (PMID: 24053775, 18209201, 20385006) and in other codons in the surrounding region suggesting that this codon as well as the surrounding region are likely important for MPZ protein function. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at