ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.188C>G (p.Ser63Cys) (rs121913585)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000390750 SCV000329683 pathogenic not provided 2015-11-03 criteria provided, single submitter clinical testing The S63C pathogenic variant in the MPZ gene has been previously reported as a de novo variant in a patient with Dejerine Sottas syndrome (Hayasaka et al., 1993). Functional studies show that mice carrying the S63C variant develop neuropathy (Wrabetz et al., 2006). S63C 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. A different amino acid substitution at the same position (S63F) and other 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, the presence of the S63C pathogenic variant
Athena Diagnostics Inc RCV000390750 SCV000614101 pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
Invitae RCV000803240 SCV000943102 pathogenic Charcot-Marie-Tooth disease, type I 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 63 of the MPZ protein (p.Ser63Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Dejerine-Sottas syndrome (PMID: 7506095). ClinVar contains an entry for this variant (Variation ID: 14169). Experimental studies using transgenic mouse models have shown that this missense change [p.Ser63Cys] creates a packing defect in the myelin sheath that leads to hypomyelination and these mice develop tremor, ataxia, weakness and muscle atrophy of hind limbs recapitulating phenotypes observed in human neuromuscular disease (PMID: 16495463, 20937820). This variant disrupts the p.Ser63 amino acid residue in MPZ. Other variant that disrupt this residue have been observed in affected individuals (PMID: 22734905, 7693130, 12402337, 8835320), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015232 SCV000035491 pathogenic Dejerine-Sottas syndrome, autosomal dominant 1993-11-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789439 SCV000928795 uncertain significance Dejerine-Sottas disease no assertion criteria provided literature only

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