ClinVar Miner

Submissions for variant NM_000530.8(MPZ):c.434A>C (p.Tyr145Ser) (rs121913603)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234112 SCV000285038 pathogenic Charcot-Marie-Tooth disease, type I 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with serine at codon 145 of the MPZ protein (p.Tyr145Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with disease in families affected with hereditary peripheral neuropathy and hereditary sensory motor neuropathy with deafness (PMID: 12845552, 12805115). ClinVar contains an entry for this variant (Variation ID: 14191). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235936 SCV000292611 pathogenic not provided 2015-07-20 criteria provided, single submitter clinical testing The Y145S missense mutation in the MPZ gene has been reported previously in association with Charcot- Marie-Tooth disease type 1B (CMT1B) (Leal et al., 2003). The Y145S missense mutation has also been reported previously in family with peripheral neuropathy and deafness (Starr et al., 2003). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y145S mutation is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. Therefore, the presence of Y145S is consistent with a diagnosis of an MPZ-related disorder
Fulgent Genetics,Fulgent Genetics RCV000763260 SCV000893898 pathogenic Charcot-Marie-Tooth disease type 2I; Charcot-Marie-Tooth disease type 2J; Charcot-Marie-Tooth disease, demyelinating, type 1b; Charcot-Marie-Tooth disease dominant intermediate d; Roussy-Lévy syndrome; Dejerine-Sottas disease; Congenital hypomyelinating neuropathy 1, autosomal recessive 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000015255 SCV000035514 pathogenic Charcot-Marie-Tooth disease, demyelinating, type 1b 2003-08-01 no assertion criteria provided literature only

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