Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000196172 | SCV000253842 | pathogenic | Charcot-Marie-Tooth disease, type I | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the MPZ protein (p.Arg98His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1 (PMID: 7688964, 8644725, 10581375, 12477701, 20215982). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14176). 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). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000376287 | SCV000329714 | pathogenic | not provided | 2022-08-30 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect on cell adhesiveness (Lee et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31211173, 33179255, 31372974, 12221176, 8797476, 7688964, 10737979, 20215982, 10581375, 11437164, 29687021, 32376792, 33726816, 20461396, 8644725, 26310628) |
Centre for Mendelian Genomics, |
RCV000415463 | SCV000492978 | likely pathogenic | Decreased nerve conduction velocity; Sensory neuropathy; Pes cavus; Distal muscle weakness; Distal lower limb amyotrophy | 2014-09-19 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics Inc | RCV000376287 | SCV000614105 | pathogenic | not provided | 2015-03-12 | criteria provided, single submitter | clinical testing | Not found in the total gnomAD dataset, and the data is high quality. Found in multiple individuals with expected phenotype for this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregates with disease in multiple families |
Ce |
RCV000376287 | SCV001249786 | pathogenic | not provided | 2021-10-01 | criteria provided, single submitter | clinical testing | |
Molecular Genetics Laboratory, |
RCV001173692 | SCV001336802 | pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
Mayo Clinic Laboratories, |
RCV000376287 | SCV001713094 | pathogenic | not provided | 2022-01-20 | criteria provided, single submitter | clinical testing | PM1, PM2, PS3, PS4 |
Ambry Genetics | RCV002433457 | SCV002747828 | pathogenic | Inborn genetic diseases | 2020-03-25 | criteria provided, single submitter | clinical testing | The p.R98H pathogenic mutation (also known as c.293G>A), located in coding exon 3 of the MPZ gene, results from a G to A substitution at nucleotide position 293. The arginine at codon 98 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with demyelinating Charcot-Marie Tooth disease and to co-segregate with disease in multiple families (Lagueny A et al. Neuromuscul. Disord., 1999 Oct;9:361-7; Ohnishi A et al. J. Neurol. Sci., 1999 Dec;171:97-109; Rouger H et al. Am. J. Hum. Genet., 1996 Mar;58:638-41). Additionally, in vitro functional studies have shown that protein with this alteration fails to localize to the cell membrane and increases the unfolded protein response in the cell (Bai Y et al. Ann Clin Transl Neurol, 2018 Apr;5:445-455; Lee YC et al. J. Neurol., 2010 Oct;257:1661-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
3billion | RCV000015239 | SCV003842081 | pathogenic | Charcot-Marie-Tooth disease type 1B | 2023-02-23 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000014176) and different missense changes at the same codon (p.Arg98Cys, p.Arg98Leu, p.Arg98Pro / ClinVar ID: VCV000014174, VCV000014175, VCV000586152) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. |
Preventiongenetics, |
RCV003398515 | SCV004103382 | pathogenic | MPZ-related condition | 2022-10-21 | criteria provided, single submitter | clinical testing | The MPZ c.293G>A variant is predicted to result in the amino acid substitution p.Arg98His. This variant has been reported in many individuals and families with Charcot-Marie-Tooth disease, type 1B (Ohnishi et al. 1999. PubMed ID: 10581375; Lee et al. 2010. PubMed ID: 20461396; Hsu et al. 2019. PubMed ID: 31211173; Volodarsky et al. 2020. PubMed ID: 32376792; Hayasaka et al. 1993. PubMed ID: 7688964; Gabreëls-Festen et al. 1996. PubMed ID: 8797476). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. |
OMIM | RCV000015239 | SCV000035498 | pathogenic | Charcot-Marie-Tooth disease type 1B | 2002-09-10 | no assertion criteria provided | literature only | |
Clinical Genetics, |
RCV000376287 | SCV002034563 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000376287 | SCV002037333 | pathogenic | not provided | no assertion criteria provided | clinical testing |