Submissions for variant NM_000304.4(PMP22):c.418T>A (p.Trp140Arg)

dbSNP: rs1555564040

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001064771	SCV001229691	likely pathogenic	Charcot-Marie-Tooth disease, type I	2022-05-18	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 PMP22 protein function. ClinVar contains an entry for this variant (Variation ID: 637842). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 11545686; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 140 of the PMP22 protein (p.Trp140Arg).
GeneDx	RCV002269313	SCV002552772	likely pathogenic	not provided	2022-07-19	criteria provided, single submitter	clinical testing	Identified in a patient with Charcot-Marie-Tooth disease in the published literature, but additional clinical information and familial segregation studies were not included (Takashima et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); 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: 11545686)
Inherited Neuropathy Consortium	RCV000790173	SCV000929564	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV003483723	SCV004228567	not provided	Hereditary liability to pressure palsies; Charcot-Marie-Tooth disease type 1E; Charcot-Marie-Tooth disease, type IA		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-07-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.