ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.233C>G (p.Ser78Trp) (rs121913601)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470689 SCV000552943 pathogenic Charcot-Marie-Tooth disease, type I 2019-11-11 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 78 of the MPZ protein (p.Ser78Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with CMT1 (PMID: 12707985). It has also been observed in an affected individual in the Invitae database. 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.Ser78Leu) has been determined to be pathogenic (PMID: 7527371, 9633821, 18347322). This suggests that the serine 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.
Athena Diagnostics Inc RCV001289097 SCV001476688 likely pathogenic not provided 2020-01-13 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.
Inherited Neuropathy Consortium RCV000789070 SCV000928419 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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