rs121913605
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5
The NM_000530.8(MPZ):c.186C>G(p.Ile62Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I62F) has been classified as Pathogenic.
Frequency
Consequence
NM_000530.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MPZ | NM_000530.8 | c.186C>G | p.Ile62Met | missense_variant | 2/6 | ENST00000533357.5 | |
MPZ | NM_001315491.2 | c.186C>G | p.Ile62Met | missense_variant | 2/6 | ||
MPZ | XM_017001321.3 | c.216C>G | p.Ile72Met | missense_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MPZ | ENST00000533357.5 | c.186C>G | p.Ile62Met | missense_variant | 2/6 | 1 | NM_000530.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251308Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2I Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 14, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 25, 2003 | - - |
Tip-toe gait Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Nov 15, 2022 | - - |
Roussy-Lévy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 27, 2019 | This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM5,PP5. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2023 | The MPZ c.186C>G; p.Ile62Met variant is reported in the literature in one individual affected with late onset Charcot-Marie-Tooth 2 syndrome (Auer-Grumbach 2003). This variant is also reported in ClinVar (Variation ID: 14194) and is found in the non-Finnish European population with an overall allele frequency of 0.0012% (3/251308 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.184A>T, p.Ile62Phe) has been reported in four related individuals with autosomal dominant motor and sensory neuropathy with focally folded myelin sheaths (Nakagawa 1999) and in vitro functional analysis of the p.Ile62Phe variant demonstrated dysregulation of adhesion function of the MPZ protein associated with abnormal myelin folding (Matsuyama 2002). Computational analyses of the p.Ile62Met, however, are uncertain whether this variant is neutral or deleterious (REVEL: 0.276). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Auer-Grumbach M et al. Late onset Charcot-Marie-Tooth 2 syndrome caused by two novel mutations in the MPZ gene. Neurology. 2003 Nov 25;61(10):1435-7. PMID: 14638973. Nakagawa M et al. A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths. Neurology. 1999 Apr 12;52(6):1271-5. PMID: 10214757. Matsuyama W et al. Altered trafficking and adhesion function of MPZ mutations and phenotypes of Charcot-Marie-Tooth disease 1B. Acta Neuropathol. 2002 May;103(5):501-8. PMID: 11935267. - |
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ile62 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10214757, 11935267). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 not expected to disrupt MPZ protein function. ClinVar contains an entry for this variant (Variation ID: 14194). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 14638973). This variant is present in population databases (rs121913605, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 62 of the MPZ protein (p.Ile62Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at