ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.233C>T (p.Ser78Leu) (rs121913601)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201182 SCV000255796 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2015-09-08 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000436362 SCV000334765 pathogenic not provided 2015-09-15 criteria provided, single submitter clinical testing
GeneDx RCV000436362 SCV000521268 pathogenic not provided 2018-12-27 criteria provided, single submitter clinical testing The S78L pathogenic variant has been reported numerous times in association with CMT (Nelis et al., 1994; Fallerini et al., 2015; Manganelli et al., 2014; Miltenberger-Miltenyi et al., 2009; Mandich et al., 2009; Mazzeo et al., 2008). The S78L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S78L pathogenic variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different amino acid substitution at this same position (S78W) and 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, S78L is interpreted to be a pathogenic variant.
Invitae RCV000546842 SCV000636239 pathogenic Charcot-Marie-Tooth disease, type I 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 78 of the MPZ protein (p.Ser78Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease type I in several families (PMID: 7527371, 18347322, 9633821, 10965800). ClinVar contains an entry for this variant (Variation ID: 14188). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Different missense substitutions at this codon (p.Ser78Leu, p.Ser78Trp) has been determined to be pathogenic (PMID: 7527371, 9633821, 18347322, 12707985, Invitae). 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.
OMIM RCV000015252 SCV000035511 pathogenic Charcot-Marie-Tooth disease, type 1b, with focally folded myelin sheaths 2000-09-01 no assertion criteria provided literature only

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