ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.188_190del (p.Ser63del) (rs879254109)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235309 SCV000293536 pathogenic not provided 2016-05-05 criteria provided, single submitter clinical testing The c.188_190delCCT pathogenic variant in the MPZ gene has been reported previously (reported as Serine 34 deletion due to alternative nomenclature) in the heterozygous state in multiple individuals with Charcot-Marie-Tooth type 1B (Kulkens et al., 1993; Miller et al., 2012). The c.188_190delCCT variant results in an in-frame deletion of Serine 63, denoted p.S63del. Functional studies have shown that the protein with the c.188_190delCCT variant is folded incorrectly, retained within the endoplasmic reticulum, and generates an unfolded protein response within the cell (Wrabetz et al., 2006; Pennuto et al., 2008). The c.188_190delCCT variant 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. We interpret c.188_190delCCT as a pathogenic variant.
Invitae RCV000535237 SCV000636238 pathogenic Charcot-Marie-Tooth disease, type I 2019-07-28 criteria provided, single submitter clinical testing This variant, c.188_190delCCT, results in the deletion of 1 amino acid from the MPZ protein (p.Ser63del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth type 1B (CMT1B) in 2 families (PMID: 22734905, 7693130). It has also been identified in an individual with CMT1B (PMID: 12402337). This variant is also known as Serine 34 del in the literature. ClinVar contains an entry for this variant (Variation ID: 246121). Mouse models have shown that this deletion results in demyelinating neuropathy that mimics the corresponding human disease. Ser63del mice have shown that Ser63del MPZ is retained in the endoplasmic reticulum where it activates the unfolded protein response (UPR) that contributes to the neuropathy (PMID: 16495463, 18255032). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015231 SCV000035490 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 1993-09-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000790083 SCV000929473 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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