ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.181G>A (p.Asp61Asn) (rs797044845)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000193325 SCV000243902 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2015-03-26 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789423 SCV000928778 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Invitae RCV000688094 SCV000815692 pathogenic Charcot-Marie-Tooth disease, type I 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 61 of the MPZ protein (p.Asp61Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with congenital hypomyelinating neuropathy (PMID: 23290023). This variant has also been reported in individuals affected with Charcot-Marie-Tooth disease (PMID: 22451207, 11484669). ClinVar contains an entry for this variant (Variation ID: 208146). Experimental studies have shown that this missense change results in increased glycosylation of the MPZ protein and impairs intracellular trafficking (PMID: 22451207). A different missense substitution at this codon (p.Asp61Gly) has been determined to be pathogenic (PMID: 10764043). This suggests that the aspartic acid 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.

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