ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.182A>G (p.Asp61Gly) (rs786204119)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168067 SCV000218721 pathogenic Charcot-Marie-Tooth disease, type I 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 61 of the MPZ protein (p.Asp61Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Charcot-Marie-Tooth disease in a large family (PMID: 10764043). ClinVar contains an entry for this variant (Variation ID: 188168). 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. This variant disrupts the p.Asp61 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 23290023, 11484669, 22451207), 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.
GeneDx RCV000236489 SCV000293160 likely pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing The D61G variant has been previously reported to segregate with CMT2 in a large family (Senderek et al., 2000). The variant is located in the P0 extracellular domain which is responsible for tetramerisation (Senderek et al., 2000). It 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. The D61G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Additionally, 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. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236489 SCV001249788 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790119 SCV000929510 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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