Submissions for variant NM_000530.8(MPZ):c.293G>A (p.Arg98His) (rs121913589)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196172	SCV000253842	pathogenic	Charcot-Marie-Tooth disease, type I	2019-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 98 of the MPZ protein (p.Arg98His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease type 1 (CMT1) in a single family (PMID: 7688964). This variant has also been reported in several unrelated CMT1 patients (PMID: 8644725, 20215982, 10581375, 12477701). ClinVar contains an entry for this variant (Variation ID: 14176). Experimental studies have shown that this variant causes cellular mislocalization of the MPZ protein (PMID: 20461396). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000376287	SCV000329714	pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing	The R98H pathogenic variant in the MPZ gene has been reported previously in individuals with Charcot-Marie-Tooth disease type 1 (Rouger et al., 1996; Ohnishi et al., 1999; Souayah et al., 2010). In muscle biopsies from individuals who carry R98H, myelin changes were seen at both extracellular and cytoplasmic appositions of Schwann cell membranes (Ohnishi et al., 1999). Functional studies show R98H leads to an attenuated adhesiveness in cells (Lee et al., 2010). The R98H variant 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 R98H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R98H as a pathogenic variant.
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 Inc	RCV000376287	SCV000614105	pathogenic	not provided	2015-03-12	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in multiple individuals with expected phenotype for this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregates with disease in multiple families
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000376287	SCV001249786	pathogenic	not provided	2018-03-01	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
OMIM	RCV000015239	SCV000035498	pathogenic	Charcot-Marie-Tooth disease, demyelinating, type 1b	2002-09-10	no assertion criteria provided	literature only