Submissions for variant NM_000530.8(MPZ):c.356A>G (p.Tyr119Cys)

dbSNP: rs879254038

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000237035	SCV000293258	likely pathogenic	not provided	2025-03-26	criteria provided, single submitter	clinical testing	Has been reported previously in at least two families with adult-onset Charcot-Marie-Tooth (CMT) disease, with some individuals also exhibiting hearing loss (PMID: 26310628, 10764043); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 26310628, 10764043, 29687021, 33179255, 34210210, 34060689, 37581289, 36203352, 20461396, 28902413)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638165	SCV000759651	pathogenic	Charcot-Marie-Tooth disease, type I	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 119 of the MPZ protein (p.Tyr119Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 10764043, 26310628; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MPZ variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 11,906 individuals referred to our laboratory for MPZ testing. ClinVar contains an entry for this variant (Variation ID: 245997). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MPZ protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MPZ function (PMID: 29687021). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000237035	SCV001249785	pathogenic	not provided	2018-10-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000237035	SCV001905519	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000237035	SCV002771870	pathogenic	not provided	2022-04-11	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant associates with disease in multiple families. Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.
Ambry Genetics	RCV004020925	SCV004994348	uncertain significance	Inborn genetic diseases	2023-12-11	criteria provided, single submitter	clinical testing	The c.356A>G (p.Y119C) alteration is located in exon 3 (coding exon 3) of the MPZ gene. This alteration results from a A to G substitution at nucleotide position 356, causing the tyrosine (Y) at amino acid position 119 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Institute of Immunology and Genetics Kaiserslautern	RCV004584640	SCV005073983	likely pathogenic	Charcot-Marie-Tooth disease type 1B	2024-06-17	criteria provided, single submitter	clinical testing	ACMG Criteria: PS3, PM1, PP1, PM2_P, PP5; Variant was found in heterozygous state
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004584640	SCV005398639	likely pathogenic	Charcot-Marie-Tooth disease type 1B	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Charcot-Marie-Tooth disease dominant intermediate D (MIM#607791), Charcot-Marie-Tooth disease, type 1B (MIM#118200), Charcot-Marie-Tooth disease, type 2I (MIM#607677), Charcot-Marie-Tooth disease, type 2J (MIM#607736), Dejerine-Sottas disease (MIM#145900), congenital hypomyelinating neuropathy 2 (MIM#618184), and Roussy-Levy syndrome (MIM#180800) (OMIM). Loss of function is associated with NMD-predicted variants while gain of function is associated with missense and protein truncation variants (PMIDs: 16495463, 30239779). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however Dejerine-Sottas disease is also caused by biallelic variants (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMIDs: 17030746, 30239779). (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Ig-like V-type extracellular domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in three families with adult-onset Charcot-Marie-Tooth disease and has been classified as pathogenic by clinical diagnostic laboratories (ClinVar; PMIDs: 10764043, 26310628). (SP) 0906 - Segregation evidence for this variant is inconclusive. There is currently insufficient information to determine segregation of this variant with disease (PMIDs: 10764043, 26310628). (I) 1010 - Functional evidence for this variant is inconclusive. Luciferase reporter constructs with the p.(Tyr119Cys) variant transfected into RT4 schwann cells did not demonstrate increased unfolded protein response (UPR) compared to WT constructs (PMID: 29687021). However, mutant constructs with other variants have also been shown to not result in a significantly increased UPR compared to the WT (PMID: 18337304). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Inherited Neuropathy Consortium	RCV000790120	SCV000929511	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only