Submissions for variant NM_000304.4(PMP22):c.233T>C (p.Leu78Pro)

dbSNP: rs1555565276

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498886	SCV000589525	likely pathogenic	not provided	2016-08-03	criteria provided, single submitter	clinical testing	The L78P variant has been previously reported in two related individuals with CMT1 (Pisciotta et al., 2009). It 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 L78P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Athena Diagnostics	RCV000518311	SCV000614674	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003581670	SCV004296749	likely pathogenic	Charcot-Marie-Tooth disease, type I	2024-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 78 of the PMP22 protein (p.Leu78Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 19909487; internal data). ClinVar contains an entry for this variant (Variation ID: 431943). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PMP22 protein function with a positive predictive value of 95%. 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.
3billion	RCV005252931	SCV005904192	uncertain significance	Charcot-Marie-Tooth disease type 1E	2023-12-27	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.88 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMP22-related disorder (ClinVar ID: VCV000431943 /PMID: 19909487). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Inherited Neuropathy Consortium	RCV000790161	SCV000929552	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only