Submissions for variant NM_000530.8(MPZ):c.90C>G (p.Ile30Met) (rs770546306)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000201151	SCV000255804	pathogenic	Charcot-Marie-Tooth disease, demyelinating, type 1b	2015-06-17	criteria provided, single submitter	clinical testing
Invitae	RCV000464045	SCV000552942	pathogenic	Charcot-Marie-Tooth disease, type I	2019-05-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 30 of the MPZ protein (p.Ile30Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Charcot-Marie-Tooth disease, type 1B and has been reported to segregate in affected families (PMID: 7694726, 26454100, Invitae database). ClinVar contains an entry for this variant (Variation ID: 217235). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Different missense substitution at this codon (p.Ile30Phe, p.Ile30Ser, p.Ile30Thr) have been identified in individuals affected with Dejerine Sottas disease and Charcot-Marie-Tooth disease (PMID: 17143884, 19259128, 20461396). This suggests that the isoleucine residue may be critical for MPZ protein function. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000712322	SCV000842788	pathogenic	not provided	2015-06-17	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789438	SCV000928793	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only

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