2-27312584-G-GC
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002437.5(MPV17):c.284dupG(p.Phe96LeufsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
MPV17
NM_002437.5 frameshift
NM_002437.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.188
Genes affected
MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-27312584-G-GC is Pathogenic according to our data. Variant chr2-27312584-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 290443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MPV17 | NM_002437.5 | c.284dupG | p.Phe96LeufsTer17 | frameshift_variant | Exon 5 of 8 | ENST00000380044.6 | NP_002428.1 | |
| MPV17 | XM_005264326.5 | c.284dupG | p.Phe96LeufsTer17 | frameshift_variant | Exon 5 of 8 | XP_005264383.1 | ||
| MPV17 | XM_017004151.2 | c.236dupG | p.Phe80LeufsTer17 | frameshift_variant | Exon 5 of 8 | XP_016859640.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251244Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135804
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727170
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GnomAD4 genome 0.0000197 AC: 3AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74352
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 16, 2021 | PVS1, PS4_moderate, PM2, PM3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 15, 2015 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 04, 2024 | 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. - |
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Pathogenic:4Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Dec 01, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Mar 22, 2022 | 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. - |
| Uncertain significance, flagged submission | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | 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. - |
Charcot-Marie-Tooth disease, axonal, type 2EE Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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