ClinVar Miner

Submissions for variant NM_000304.4(PMP22):c.185T>G (p.Leu62Arg) (rs756046682)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168113 SCV000218769 uncertain significance Charcot-Marie-Tooth disease, type I 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 62 of the PMP22 protein (p.Leu62Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hereditary motor neuropathy (PMID: 26392352). 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765330 SCV000896592 uncertain significance Guillain-Barre syndrome, familial; Hereditary liability to pressure palsies; Roussy-Lévy syndrome; Charcot-Marie-Tooth disease and deafness; Charcot-Marie-Tooth disease, type IA; Dejerine-Sottas disease 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194158 SCV001363467 uncertain significance not specified 2019-12-19 criteria provided, single submitter clinical testing Variant summary: PMP22 c.185T>G (p.Leu62Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.185T>G has been reported in the literature in an individual affected with hereditary motor neuropathy (Antoniadi_2015). This report does not provide unequivocal conclusions about association of the variant with PMP22-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics Inc RCV001657933 SCV001879482 uncertain significance not provided 2021-01-19 criteria provided, single submitter clinical testing

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