rs879253858
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM1PM2PM5PP5_Very_Strong
The NM_000530.8(MPZ):c.403A>T(p.Ile135Leu) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I135M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000530.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPZ | NM_000530.8 | c.403A>T | p.Ile135Leu | missense_variant | 3/6 | ENST00000533357.5 | |
MPZ | NM_001315491.2 | c.403A>T | p.Ile135Leu | missense_variant | 3/6 | ||
MPZ | XM_017001321.3 | c.433A>T | p.Ile145Leu | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPZ | ENST00000533357.5 | c.403A>T | p.Ile135Leu | missense_variant | 3/6 | 1 | NM_000530.8 | P1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 1B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000861910). A different missense change at the same codon (p.Ile135Thr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014172). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Charcot-Marie-Tooth disease, type I Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2019 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ile135 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8664899). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with Dejerine-Sottas syndrome (PMID: 12090401). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with leucine at codon 135 of the MPZ protein (p.Ile135Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at