rs121913590
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000530.8(MPZ):c.292C>T(p.Arg98Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98L) has been classified as Likely pathogenic.
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.292C>T | p.Arg98Cys | missense_variant | 3/6 | ENST00000533357.5 | |
MPZ | NM_001315491.2 | c.292C>T | p.Arg98Cys | missense_variant | 3/6 | ||
MPZ | XM_017001321.3 | c.322C>T | p.Arg108Cys | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPZ | ENST00000533357.5 | c.292C>T | p.Arg98Cys | missense_variant | 3/6 | 1 | NM_000530.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 29
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461806Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727204
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151976Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1AN XY: 74232
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 1B Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 06, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 21, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jun 05, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PM6 strong, PP3 supporting - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | MPZ: PS2, PM1, PM2, PM5, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2022 | Published functional studies demonstrate a damaging effect; R98C results in reduced transport of the MPZ protein to the plasma membrane (Lee et al., 2010; Saporta et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 12477701, 23250879, 9168174, 9187667, 20461396, 19293842, 8816708, 8797476, 17172621, 10093067, 8644725, 21840889, 28704293, 29687021, 15050444, 10207934, 31211173, 31827005, 33825325, 26310628, 24077912, 22689911) - |
Charcot-Marie-Tooth disease, type I Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 98 of the MPZ protein (p.Arg98Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease and Dejerine-Sottas syndrome (PMID: 8644725, 8797476, 9168174, 20461396, 21840889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MPZ function (PMID: 20461396, 22689911). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at