ClinVar Miner

Submissions for variant NM_002437.5(MPV17):c.461+1G>C

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002651443 SCV003523968 pathogenic not provided 2022-09-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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. 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. Studies have shown that disruption of this splice site alters MPV17 gene expression (PMID: 31664948). Disruption of this splice site has been observed in individuals with Mitochondrial DNA depletion syndrom (PMID: 23714749, 31664948). This variant is not present in population databases (gnomAD no frequency). 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.
Fulgent Genetics, Fulgent Genetics RCV005028319 SCV005655946 pathogenic Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); Charcot-Marie-Tooth disease, axonal, type 2EE 2024-06-20 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004733604 SCV005362388 pathogenic MPV17-related disorder 2024-06-19 no assertion criteria provided clinical testing The MPV17 c.461+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous state to be causative for mitochondrial DNA depletion syndrome (Uusimaa et al. 2014. PubMed ID: 23714749; Mahjoub et al. 2019. PubMed ID: 31664948). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice donor site in MPV17 are expected to be pathogenic. This variant is interpreted as pathogenic.

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