Submissions for variant NM_000530.8(MPZ):c.233C>T (p.Ser78Leu)

dbSNP: rs121913601

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000436362	SCV000255796	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant Charcot-Marie-Tooth disease and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. In some published literature, this variant is referred to as p.Ser49Leu. The variant is located in a region that is considered important for protein function and/or structure.
Eurofins Ntd Llc (ga)	RCV000436362	SCV000334765	pathogenic	not provided	2015-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000436362	SCV000521268	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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, 26135405, 26481167, 25429913, 19691535, 19293842, 7527371, 19259128, 11545686, 10965800, 11437164, 9633821, 9187667, 11835375, 12497641, 10093067, 7550231, 18347322, 26406915, 18422810, 29687021, 32376792, 33825325, 12707985, 9883862, 20461396)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546842	SCV000636239	pathogenic	Charcot-Marie-Tooth disease, type I	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 78 of the MPZ protein (p.Ser78Leu). 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 type I (PMID: 7527371, 9633821, 10965800, 18347322). 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: 14188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Ser78 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7527371, 9633821, 12707985, 18347322; internal data). 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173691	SCV001336801	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000436362	SCV001446790	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000436362	SCV004009899	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MPZ: PS4, PM1, PM2, PM5, PP1
OMIM	RCV000015252	SCV000035511	pathogenic	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B, WITH FOCALLY FOLDED MYELIN SHEATHS	2000-09-01	no assertion criteria provided	literature only