Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000196172 | SCV000253842 | pathogenic | Charcot-Marie-Tooth disease, type I | 2019-07-31 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with histidine at codon 98 of the MPZ protein (p.Arg98His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease type 1 (CMT1) in a single family (PMID: 7688964). This variant has also been reported in several unrelated CMT1 patients (PMID: 8644725, 20215982, 10581375, 12477701). ClinVar contains an entry for this variant (Variation ID: 14176). Experimental studies have shown that this variant causes cellular mislocalization of the MPZ protein (PMID: 20461396). For these reasons, this variant has been classified as Pathogenic. |
Gene |
RCV000376287 | SCV000329714 | pathogenic | not provided | 2017-05-11 | criteria provided, single submitter | clinical testing | The R98H pathogenic variant in the MPZ gene has been reported previously in individuals with Charcot-Marie-Tooth disease type 1 (Rouger et al., 1996; Ohnishi et al., 1999; Souayah et al., 2010). In muscle biopsies from individuals who carry R98H, myelin changes were seen at both extracellular and cytoplasmic appositions of Schwann cell membranes (Ohnishi et al., 1999). Functional studies show R98H leads to an attenuated adhesiveness in cells (Lee et al., 2010). The R98H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R98H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R98H as a pathogenic variant. |
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 | 2018-03-01 | criteria provided, single submitter | clinical testing | |
Molecular Genetics Laboratory, |
RCV001173692 | SCV001336802 | pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
OMIM | RCV000015239 | SCV000035498 | pathogenic | Charcot-Marie-Tooth disease, demyelinating, type 1b | 2002-09-10 | no assertion criteria provided | literature only |