ClinVar Miner

Submissions for variant NM_002677.5(PMP2):c.155T>C (p.Ile52Thr)

dbSNP: rs1563518388
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000736031 SCV000920876 likely pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1G 2018-11-01 criteria provided, single submitter research We found a PMP2 variant c.155T > C, p.(Ile52Thr) that segregates with the disease in 4 affected individuals of a multi-generational family.
Ambry Genetics RCV001267025 SCV001445206 likely pathogenic Inborn genetic diseases 2021-07-21 criteria provided, single submitter clinical testing The c.155T>C (p.I52T) alteration is located in coding exon 2 of the PMP2 gene. This alteration results from a T to C substitution at nucleotide position 155, causing the isoleucine (I) at amino acid position 52 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PMP2 c.155T>C alteration was not observed, with coverage at this position. This alteration has been detected in multiple individuals with Charcot-Marie-Tooth (CMT) disease type 1 and has been found to co-segregate with disease in different families (Motley, 2016; Punetha, 2018). The p.I52 amino acid is located in the highly-conserved ligand-binding core domain of PMP2 (Hong, 2016; Motley, 2016). Functional analysis showed the p.I52T alteration affects protein aggregation tendency and dynamics (Ruskamo, 2017). The p.I52T alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000736031 SCV001548531 likely pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1G 2021-02-10 criteria provided, single submitter clinical testing This PMP2 variant has been identified in multiple multi-generation families segregating autosomal dominant Charcot-Marie-Tooth disease including one instance where it was reported to be a de novo change in an affected individual. c.155T>C is absent from a large population database. This variant has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging, however these algorithms are optimized for loss of function variants. The isoleucine residue at this position is conserved across most species assessed and there is functional evidence that this substitution may result in decreased myelin stability and altered protein dynamics. We consider c.155T>C to be likely pathogenic.
Centogene AG - the Rare Disease Company RCV000736031 SCV002059495 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1G 2019-07-19 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000736031 SCV002581030 likely pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1G 2022-07-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535440 SCV003440895 pathogenic not provided 2025-01-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 52 of the PMP2 protein (p.Ile52Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 27009151, 30249361). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 599406). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PMP2 function (PMID: 28747762). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000736031 SCV000864250 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1G 2025-02-19 no assertion criteria provided literature only

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