Submissions for variant NM_000530.8(MPZ):c.371C>T (p.Thr124Met)

dbSNP: rs121913595

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517355	SCV000614106	pathogenic	not provided	2020-10-09	criteria provided, single submitter	clinical testing	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. 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.
Invitae	RCV000638155	SCV000759641	pathogenic	Charcot-Marie-Tooth disease, type I	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 124 of the MPZ protein (p.Thr124Met). 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: 9452091, 10923043, 12207153, 12948789, 15159512, 16279991, 19629567, 25720167, 26234237). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14181). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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: 18337304, 20461396). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763262	SCV000893900	pathogenic	Charcot-Marie-Tooth disease type 2I; Charcot-Marie-Tooth disease type 2J; Charcot-Marie-Tooth disease type 1B; Charcot-Marie-Tooth disease dominant intermediate D; Roussy-Lévy syndrome; Dejerine-Sottas disease; Charcot-Marie-Tooth disease type 4E	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000517355	SCV001249783	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	MPZ: PM1, PM2, PP1:Moderate, PS3:Moderate, PS4:Moderate
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262744	SCV001440723	pathogenic	Charcot-Marie-Tooth disease dominant intermediate D	2019-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000517355	SCV002520050	pathogenic	not provided	2021-08-19	criteria provided, single submitter	clinical testing	PP1, PM1, PM2, PS3_moderate, PS4
GeneDx	RCV000517355	SCV002540333	pathogenic	not provided	2022-06-29	criteria provided, single submitter	clinical testing	Identified in multiple unrelated patients with Charcot-Marie-Tooth (Yoshihara et al., 2000; Gallardo et al., 2009; Liu et al., 2013; Bergamin et al., 2014); Published functional studies demonstrate a damaging effect (Grandis et al., 2008; Lee et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 15159512, 19928689, 24819634, 18563718, 18337304, 20461396, 19629567, 10835936, 9452091, 25720167, 26234237, 16279991, 24028194, 15377707, 10071056, 34210210, 33825325, 22820753, 20301384, 16775239, 12911457, 31827005, 30018047, 29516875, 10329755, 25802885, 29687021, 31211173, 12948789, 12207153, 10764043, 26310628, 10923043)
Ambry Genetics	RCV002345245	SCV002623128	pathogenic	Inborn genetic diseases	2019-10-16	criteria provided, single submitter	clinical testing	The p.T124M variant (also known as c.371C>T), located in coding exon 3 of the MPZ gene, results from a C to T substitution at nucleotide position 371. The threonine at codon 124 is replaced by methionine, an amino acid with similar properties. This alteration has been described in multiple unrelated individuals with axonal Charcot-Marie-Tooth disease type 2J as well as segregating with disease through multiple families. Patients typically present in adulthood with weakness and pains in lower limbs, sensory dysfunction, relatively well preserved nerve conduction velocities, axonal disease present on muscle biopsy, and slightly elevated CK levels. Other commonly reported symptoms include deafness and pupillary abnormalities (Baloh RH et al. Neurology, 2004 May;62:1905-6; Chapon F et al. J. Neurol. Neurosurg. Psychiatry, 1999 Jun;66:779-8; De Jonghe P et al. Brain, 1999 Feb;122 ( Pt 2):281-90; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Misu K et al. Rinsho Shinkeigaku, 2000 Feb;40:149-54; Senderek J et al. Brain Pathol., 2000 Apr;10:235-48; Tokuda N et al. Intern. Med., 2015 Aug;54:1919-22). Although functional data suggest protein with this alteration is transported normally to the plasma membrane, there is a reduction in MPZ-mediated intercellular adhesion as well as abnormal glycosylation (Bai Y et al. Ann Clin Transl Neurol, 2018 Apr;5:445-455; Grandis M et al. Hum. Mol. Genet., 2008 Jul;17:1877-89). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000015244	SCV000035503	pathogenic	Charcot-Marie-Tooth disease type 2J	2006-06-15	no assertion criteria provided	literature only
OMIM	RCV000015245	SCV000035504	pathogenic	Charcot-Marie-Tooth disease type 1B	2006-06-15	no assertion criteria provided	literature only
GeneReviews	RCV000015245	SCV000057834	not provided	Charcot-Marie-Tooth disease type 1B		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000192248	SCV000929509	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV001262744	SCV001759992	likely pathogenic	Charcot-Marie-Tooth disease dominant intermediate D		no assertion criteria provided	clinical testing
Chongqing Key Laboratory of Neurology, First Affiliated Hospital of Chongqing Medical University	RCV002245981	SCV002512139	pathogenic	Distal hereditary motor neuropathy type 2		no assertion criteria provided	clinical testing