ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.293G>A (p.Arg98His) (rs121913589)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000015239 SCV000255800 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2015-03-12 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000376287 SCV000614105 pathogenic not provided 2015-03-12 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana 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
GeneDx 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.
Invitae RCV000196172 SCV000253842 pathogenic Charcot-Marie-Tooth disease, type I 2018-10-09 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.
OMIM RCV000015239 SCV000035498 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2002-09-10 no assertion criteria provided literature only

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