Submissions for variant NM_007289.4(MME):c.1342C>T (p.Arg448Ter)

gnomAD frequency: 0.00008  dbSNP: rs149905705

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000614012	SCV000711797	pathogenic	Congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization	2016-03-28	criteria provided, single submitter	clinical testing	The p.Arg448X variant in MME has been reported in one compound heterozygote moth er with NEP deficiency who had a child with neonatal membranous glomerulopathy ( Debiec 2004). This variant has also been identified in 4/120,898 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149905705). Although this variant has been seen in the general population, it s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 448, whi ch is predicted to lead to a truncated or absent protein. Loss of function of th e MME gene in a mother is associated with fetomaternal alloimmunisation leading to fetal membranous glomerulopathy when a fetus has the normal MME gene copy. In summary, this variant meets our criteria to be classified as pathogenic for NEP deficiency (responsible for alloimmune antenatal membranous nephropathy) bas ed upon its co-occurrence with another disease-causing variant in an affected in dividual and the predicted functional impact.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196533	SCV001367141	pathogenic	Spinocerebellar ataxia 43	2019-11-14	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001783108	SCV002128951	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg448*) in the MME gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MME are known to be pathogenic (PMID: 26991897). This variant is present in population databases (rs149905705, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with Charcot-Marie-Tooth disease or neutral endopeptidase deficiency (PMID: 15464186, 27588448, 30415211). ClinVar contains an entry for this variant (Variation ID: 504903). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001783108	SCV002756705	pathogenic	not provided	2022-05-19	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32657593, 25525159, 34426522, 31589614, 34480178, 34307994, 31429185, 35304567, 15800120, 26991897, 25565308, 15464186, 27588448, 30609409, 30415211)
CeGaT Center for Human Genetics Tuebingen	RCV001783108	SCV005436207	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	MME: PM3:Very Strong, PVS1, PM2
Fulgent Genetics, Fulgent Genetics	RCV005034189	SCV005664976	pathogenic	Charcot-Marie-Tooth disease axonal type 2T; Spinocerebellar ataxia 43	2024-03-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751626	SCV005362341	pathogenic	MME-related disorder	2024-09-21	no assertion criteria provided	clinical testing	The MME c.1342C>T variant is predicted to result in premature protein termination (p.Arg448*). This variant was first reported in the compound heterozygous state in an individual with neutral endopeptidase deficiency who, in a retrospective study, developed Charcot-Marie-Tooth disease type 2 (CMT2, Debiec et al. 2004. PubMed ID: 15464186; Nortier et al. 2021. PubMed ID: 34307994). This variant has also been reported in the compound heterozygous or homozygous state in several unrelated individuals with CMT2 (Lupo et al. 2018. PubMed ID: 30415211), as well as autosomal recessive distal hereditary motor neuropathy (Hong et al. 2019. PubMed ID: 31429185). In addition, this variant has been reported in the heterozygous state in an individual with late-onset axonal neuropathies (individual US6/II-1 in Auer-Grumbach et al. 2016. PubMed ID: 27588448). In vitro functional studies using HEK293 cells demonstrated that expression of this variant results in significantly decreased mRNA levels and enzymatic activity (Hong et al. 2019. PubMed ID: 31429185). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD, and has been consistently interpreted as pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/504903/). Nonsense variants in MME are expected to be pathogenic. This variant is interpreted as pathogenic.