Submissions for variant NM_000530.8(MPZ):c.404T>C (p.Ile135Thr)

dbSNP: rs121913587

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425572	SCV000521267	pathogenic	not provided	2021-12-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29627640, 21107784, 9055797, 10737979, 29687021, 32959227, 33179255, 8664899, 26310628, 20461396)
3billion	RCV001807729	SCV002058370	likely pathogenic	Dejerine-Sottas disease	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (ClinVar ID: VCV000014172, PMID:8664899, PS1). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID_8664899, PM6_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000861910, PMID:8797476,22018721,30340945, PM5_M). A missense variant is a common mechanism associated with Dejerine-Sottas disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005089261	SCV005834030	pathogenic	Charcot-Marie-Tooth disease, type I	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 135 of the MPZ protein (p.Ile135Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 8664899, 10737979, 21107784). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14172). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MPZ protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MPZ function (PMID: 29687021). This variant disrupts the p.Ile135 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12090401; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015235	SCV000035494	pathogenic	Charcot-Marie-Tooth disease type 1B	1996-01-01	no assertion criteria provided	literature only