Submissions for variant NM_000530.8(MPZ):c.332C>G (p.Ser111Cys) (rs1553259663)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523011	SCV000617781	likely pathogenic	not provided	2017-08-10	criteria provided, single submitter	clinical testing	A variant that is likely pathogenic has been identified in the MPZ gene. The S111C variant has been previously reported in several individuals with a clinical diagnosis of CMT (Mandich et al., 2009, Manganelli et al., 2014, Sanmaneechai et al., 2015). The S111C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S111C 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants at the same (S111P) and in nearby residues (D109N/E, G110D, I112T) have been reported in Human Gene Mutation Database in association with MPZ-related neuropathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000704378	SCV000833325	likely pathogenic	Charcot-Marie-Tooth disease, type I	2018-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine with cysteine at codon 111 of the MPZ protein (p.Ser111Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 19293842, 26310628, 25429913). ClinVar contains an entry for this variant (Variation ID: 449538). 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. A different missense substitution at this codon (p.Ser111Phe, also referred to as p.Ser121Phe) has been reported in an individual affected with Charcot-Marie-Tooth disease (PMID: 22176150). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inherited Neuropathy Consortium	RCV000790095	SCV000929485	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only

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