Submissions for variant NM_002437.5(MPV17):c.280-1dup

dbSNP: rs766160589

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000486235	SCV000345002	pathogenic	not provided	2016-08-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000486235	SCV000565695	pathogenic	not provided	2015-06-15	criteria provided, single submitter	clinical testing	The c.284dupG variant ispredicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Although this duplication has not been previously reported to our knowledge, itis expected to be a pathogenic variant.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000265576	SCV000746014	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2017-12-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000486235	SCV001585137	pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe96Leufs*17) in the MPV17 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). This variant is present in population databases (rs766160589, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of mitochondrial DNA maintenance defect (PMID: 27848944, 29282788). ClinVar contains an entry for this variant (Variation ID: 290443). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000265576	SCV002318580	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2022-03-22	criteria provided, single submitter	clinical testing	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/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000290443, PMID:27848944). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000198). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Mayo Clinic Laboratories, Mayo Clinic	RCV000486235	SCV002520078	pathogenic	not provided	2021-04-16	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2, PM3
Revvity Omics, Revvity	RCV000486235	SCV003819652	pathogenic	not provided	2022-07-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469248	SCV004193762	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2EE	2024-03-28	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000265576	SCV005042971	uncertain significance	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2023-05-20	criteria provided, single submitter	clinical testing	The observed frameshift c.284dup(p.Phe96LeufsTer17) variant in MPV17 gene has been reported previously in homozygous state in individual(s) affected with mitochondrial DNA maintenance defects (El-Hattab et al., 2018). This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). This variant causes a frameshift starting with codon Phenylalanine 96, changes this amino acid to Leucine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe96LeufsTer17. This variant is predicted to cause loss of normal protein function through protein truncation. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MPV17 are known to be pathogenic (Uusimaa et al., 2014). For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
Natera, Inc.	RCV000265576	SCV001462525	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2020-09-16	no assertion criteria provided	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000265576	SCV004807597	uncertain significance	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2024-03-29	flagged submission	clinical testing