Submissions for variant NM_000530.8(MPZ):c.293G>A (p.Arg98His)

gnomAD frequency: 0.00001  dbSNP: rs121913589

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196172	SCV000253842	pathogenic	Charcot-Marie-Tooth disease, type I	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the MPZ protein (p.Arg98His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease type 1 (PMID: 7688964, 8644725, 10581375, 12477701, 20215982). 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: 14176). 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) indicates that this missense variant is expected to disrupt MPZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MPZ function (PMID: 20461396). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000376287	SCV000329714	pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on cell adhesiveness (PMID: 20461396); 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: 31211173, 33179255, 31372974, 12221176, 8797476, 7688964, 10737979, 20215982, 10581375, 11437164, 29687021, 32376792, 33726816, 36203352, 37273706, 29136549, 10545037, 37581289, 15729519, 34925207, 12477701, 26310628, 20461396, 8644725, 21840889, 22689911)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415463	SCV000492978	likely pathogenic	Decreased nerve conduction velocity; Sensory neuropathy; Pes cavus; Distal muscle weakness; Distal lower limb amyotrophy	2014-09-19	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000376287	SCV000614105	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with autosomal dominant Charcot-Marie-Tooth disease. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 20461396, 29687021) The variant is located in a region that is considered important for protein function and/or structure. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease.
CeGaT Center for Human Genetics Tuebingen	RCV000376287	SCV001249786	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173692	SCV001336802	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000376287	SCV001713094	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	PM1, PM2, PS3, PS4
Ambry Genetics	RCV002433457	SCV002747828	pathogenic	Inborn genetic diseases	2020-03-25	criteria provided, single submitter	clinical testing	The p.R98H pathogenic mutation (also known as c.293G>A), located in coding exon 3 of the MPZ gene, results from a G to A substitution at nucleotide position 293. The arginine at codon 98 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with demyelinating Charcot-Marie Tooth disease and to co-segregate with disease in multiple families (Lagueny A et al. Neuromuscul. Disord., 1999 Oct;9:361-7; Ohnishi A et al. J. Neurol. Sci., 1999 Dec;171:97-109; Rouger H et al. Am. J. Hum. Genet., 1996 Mar;58:638-41). Additionally, in vitro functional studies have shown that protein with this alteration fails to localize to the cell membrane and increases the unfolded protein response in the cell (Bai Y et al. Ann Clin Transl Neurol, 2018 Apr;5:445-455; Lee YC et al. J. Neurol., 2010 Oct;257:1661-8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
3billion, Medical Genetics	RCV000015239	SCV003842081	pathogenic	Charcot-Marie-Tooth disease type 1B	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000014176) and different missense changes at the same codon (p.Arg98Cys, p.Arg98Leu, p.Arg98Pro / ClinVar ID: VCV000014174, VCV000014175, VCV000586152) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV004528112	SCV004103382	pathogenic	MPZ-related disorder	2022-10-21	criteria provided, single submitter	clinical testing	The MPZ c.293G>A variant is predicted to result in the amino acid substitution p.Arg98His. This variant has been reported in many individuals and families with Charcot-Marie-Tooth disease, type 1B (Ohnishi et al. 1999. PubMed ID: 10581375; Lee et al. 2010. PubMed ID: 20461396; Hsu et al. 2019. PubMed ID: 31211173; Volodarsky et al. 2020. PubMed ID: 32376792; Hayasaka et al. 1993. PubMed ID: 7688964; Gabreëls-Festen et al. 1996. PubMed ID: 8797476). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000015239	SCV000035498	pathogenic	Charcot-Marie-Tooth disease type 1B	2002-09-10	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV000376287	SCV002034563	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000376287	SCV002037333	pathogenic	not provided		no assertion criteria provided	clinical testing