Submissions for variant NM_000530.8(MPZ):c.103G>A (p.Asp35Asn) (rs121913596)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000558954	SCV000636237	pathogenic	Charcot-Marie-Tooth disease, type I	2017-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 35 of the MPZ protein (p.Asp35Asn). 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 segregate with Charcot MarieTooth disease (CMT) in a single family (PMID: 24444136) and has been reported in several individuals with CMT (PMID: 20385006, 24053775, 23106488). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different variant (c.103G>T) giving rise to (p.Asp35ty) has been reported in a family affected with CMT (PMID: 10406984), indicating that this residue may be critical for protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar	RCV000995582	SCV001149841	pathogenic	Charcot-Marie-Tooth disease type 2I	2019-10-09	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV001093015	SCV001249790	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000790058	SCV000929448	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only