Submissions for variant NM_007289.4(MME):c.467del (p.Pro156fs)

dbSNP: rs749320057

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489776	SCV000577528	pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing	Reported to segregate with disease in two unrelated families with autosomal dominant late-onset peripheral neuropathy (Auer-Grumbach et al., 2016); Frameshift 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: 25565308, 34758253, 15464186, 27588448, 30415211, 31974930, 34307994, 31589614, 33726816, 32345996, 31429185, 20692264, 35318247)
CeGaT Center for Human Genetics Tuebingen	RCV000489776	SCV001247099	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	MME: PVS1, PP1:Strong
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196532	SCV001367140	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,PM1,PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489776	SCV001412175	pathogenic	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro156Leufs*14) 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 (rs749320057, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with late-onset axonal Charcot-Marie-Tooth disease, and alloimmune antenatal membranous nephropathy (PMID: 15464186, 25565308, 27588448). ClinVar contains an entry for this variant (Variation ID: 426945). For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000489776	SCV001450210	likely pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000255813	SCV001934509	pathogenic	Charcot-Marie-Tooth disease axonal type 2T	2022-04-27	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_SUP, PP1
Revvity Omics, Revvity	RCV000489776	SCV002017517	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000255813	SCV002521647	pathogenic	Charcot-Marie-Tooth disease axonal type 2T	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000426945 / PMID: 15464186 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000255813	SCV002580168	pathogenic	Charcot-Marie-Tooth disease axonal type 2T	2022-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000255813	SCV004803410	pathogenic	Charcot-Marie-Tooth disease axonal type 2T	2024-01-15	criteria provided, single submitter	clinical testing	Variant summary: MME c.467delC (p.Pro156LeufsX14) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00026 in 250084 control chromosomes (gnomAD). c.467delC has been reported in the literature in multiple individuals affected with Charcot-Marie Disease Axonal Type 2T (Hoyer_2022). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 35318247). ClinVar contains an entry for this variant (Variation ID: 426945). Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV003993985	SCV004812516	pathogenic	Charcot-Marie-Tooth disease type 2T	2023-06-15	criteria provided, single submitter	clinical testing	This sequence change in MME is a frameshift variant predicted to cause a premature stop codon, p.(Pro156Leufs*14), in biologically relevant exon 6/23 leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PMID: 33144514, 27588448). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.07% (25/35,256 alleles) in the Latino/Admixed American population. This variant has been reported in the context of both recessive and dominant (dominant risk factor with incomplete penetrance) inheritance patterns for Charcot-Marie-Tooth (CMT) disease (PMID: 33144514). The variant has been reported to segregate with CMT in multiple families with evidence for semi-dominant inheritance (PMID: 27588448, 33144514, 35318247). A significant reduction in neprilysin levels has been reported in the adipose tissue and blood plasma of heterozygous carriers compared to controls (PMID: 27588448). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000489776	SCV005199154	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000489776	SCV005413622	pathogenic	not provided	2023-09-07	criteria provided, single submitter	clinical testing	PP1_strong, PM3_strong, PS3_supporting, PS4, PVS1
Institute of Human Genetics, University Hospital Muenster	RCV004797819	SCV005419363	pathogenic	See cases	2024-08-16	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PS3,PS4
Fulgent Genetics, Fulgent Genetics	RCV005034029	SCV005664975	pathogenic	Charcot-Marie-Tooth disease axonal type 2T; Spinocerebellar ataxia 43	2024-03-07	criteria provided, single submitter	clinical testing
OMIM	RCV000255813	SCV000322710	risk factor	Charcot-Marie-Tooth disease axonal type 2T	2016-10-06	no assertion criteria provided	literature only
Genomics England Pilot Project, Genomics England	RCV000255813	SCV001760109	pathogenic	Charcot-Marie-Tooth disease axonal type 2T		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000489776	SCV001929594	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000489776	SCV001967420	likely pathogenic	not provided		no assertion criteria provided	clinical testing