ClinVar Miner

Submissions for variant NM_002437.5(MPV17):c.461+2T>C

gnomAD frequency: 0.00015  dbSNP: rs138199394
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000734726 SCV000862890 pathogenic not provided 2018-08-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000734726 SCV003447194 pathogenic not provided 2024-10-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the MPV17 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs138199394, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 23714749, 31664948). ClinVar contains an entry for this variant (Variation ID: 598353). Studies have shown that disruption of this splice site alters MPV17 gene expression (PMID: 31664948). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MPV17 protein in which other variant(s) (p.Ser170Phe) have been observed in individuals with MPV17-related conditions (PMID: 19520594). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV003465670 SCV004193735 likely pathogenic Charcot-Marie-Tooth disease, axonal, type 2EE 2024-02-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000734726 SCV005413181 likely pathogenic not provided 2023-10-20 criteria provided, single submitter clinical testing PM2_moderate, PM5, PVS1_moderate
Fulgent Genetics, Fulgent Genetics RCV005029401 SCV005655945 likely pathogenic Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); Charcot-Marie-Tooth disease, axonal, type 2EE 2024-01-12 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004723149 SCV005336978 likely pathogenic MPV17-related disorder 2024-03-11 no assertion criteria provided clinical testing The MPV17 c.461+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.036% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in MPV17 are expected to be pathogenic. Of note, another nucleotide change within the same consensus site (c.461+1G>C) has been reported in the homozygous state in a patient with mitochondrial DNA depletion syndrome (Uusimaa et al. 2014. PubMed ID: 23714749). Based on this evidence, the c.461+2T>C variant is interpreted as likely pathogenic.

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