ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.703AAG[1] (p.Lys236del)

dbSNP: rs755446743
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517719 SCV000614115 likely pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing
GeneDx RCV000517719 SCV000617778 likely pathogenic not provided 2021-12-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on MPZ protein properties in vitro (Raasakka et al., 2019).; In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12207932, 15716547, 26310628, 20800346, 28364294, 21336783, 29687021, 31173589, 33179255, 32376792, 20461396, 33359733)
Invitae RCV000819196 SCV000959843 pathogenic Charcot-Marie-Tooth disease, type I 2023-12-25 criteria provided, single submitter clinical testing This variant, c.706_708del, results in the deletion of 1 amino acid(s) of the MPZ protein (p.Lys236del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs755446743, gnomAD 0.006%). This variant has been observed in individuals with late-onset Charcot-Marie-Tooth disease (PMID: 12207932, 15716547). It has also been observed to segregate with disease in related individuals. This variant is also known as K263Del. ClinVar contains an entry for this variant (Variation ID: 447734). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MPZ function (PMID: 29687021, 31173589). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre RCV000789487 SCV001336809 likely pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000517719 SCV001480143 likely pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV002367719 SCV002662999 uncertain significance Inborn genetic diseases 2023-01-09 criteria provided, single submitter clinical testing The c.706_708delAAG variant (also known as p.K236del) is located in coding exon 6 of the MPZ gene. This variant results from an in-frame AAG deletion at nucleotide positions 706 to 708. This results in the in-frame deletion of a lysine at codon 236. This alteration has been previously reported in multiple families with features of autosomal dominant, adult onset Charcot-Marie-Tooth disease; however, the phenotype reported in one family shows variable penetrance with symptoms ranging from being asymptomatic to having foot deformities, pedal numbness, and muscle cramps (Sowden JE et al. J. Neurol. Neurosurg. Psychiatry. 2005 Mar;76:442-4; Street VA et al. Neuromuscul. Disord. 2002 Oct;12:643-50; Volodarsky M et al. J Med Genet. 2021 Apr;58:284-288). Overall, functional studies suggest that the protein is mislocalized to the cytoplasm, alters protein-lipid interactions, and activates the unfolded protein response in vitro; however, additional evidence is needed to confirm these results (Bai Y et al. Ann Clin Transl Neurol. 2018 Apr;5:445-455; Raasakka A et al. PLoS One. 2019 Jun;14:e0216833). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003147499 SCV003835464 likely pathogenic Charcot-Marie-Tooth disease type 2I 2022-10-06 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789487 SCV000928843 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000845000 SCV000986830 not provided Charcot-Marie-Tooth disease type 2J; Charcot-Marie-Tooth disease type 1B; Dejerine-Sottas disease; Congenital hypomyelinating neuropathy no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 07/27/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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