ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.293G>C (p.Arg98Pro) (rs121913589)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000015237 SCV000255801 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2014-09-12 criteria provided, single submitter clinical testing
Invitae RCV000638160 SCV000759646 pathogenic Charcot-Marie-Tooth disease, type I 2020-03-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 98 of the MPZ protein (p.Arg98Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease type 1 (PMID: 8644725). ClinVar contains an entry for this variant (Variation ID: 14174). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Arg98His) has been determined to be pathogenic (PMID: 8644725, 20461396, 10581375, 20215982). This suggests that the arginine residue is critical for MPZ protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000949 SCV001158048 pathogenic none provided 2020-04-21 criteria provided, single submitter clinical testing The MPZ c.293G>C; p.Arg98Pro variant (rs121913589) is reported in the literature in a family affected with Charcot-Marie-Tooth syndrome, where it co-segregated with disease in six affected individuals (Rouger 1996). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 14174). The arginine at codon 98 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (His, Cys, and Ser) have been reported in individuals with Charcot-Marie-Tooth syndrome or Dejerine-Sottas disease and are considered pathogenic (Rouger 1996, Warner 1996). Based on available information, this variant is considered to be pathogenic. References: Rouger H et al. High frequency of mutations in codon 98 of the peripheral myelin protein P0 gene in 20 French CMT1 patients. Am J Hum Genet. 1996 Mar;58(3):638-41. Warner LE et al. Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron. 1996 Sep;17(3):451-60.
OMIM RCV000015237 SCV000035496 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 1996-03-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000790115 SCV000929505 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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