Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Neuberg Centre For Genomic Medicine, |
RCV001823646 | SCV002073245 | likely pathogenic | Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) | 2023-05-20 | criteria provided, single submitter | clinical testing | The missense c.388G>C (p.Ala130Pro) variant in the MPV17 gene has been reported previously in MPV17 mutation–related mitochondrial DNA depletion syndrome (Samanta, Arghya et al., 2023) .The variant has been reported with allele frequency of 0.0003% in gnomAD Exomes. It is submitted to ClinVar as Uncertain Significance. This gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease. The amino acid Alanine at position 130 is changed to a Proline changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen - Damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ala130Pro in MPV17 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004770219 | SCV005381777 | uncertain significance | not specified | 2024-08-26 | criteria provided, single submitter | clinical testing | Variant summary: MPV17 c.388G>C (p.Ala130Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.388G>C has been reported in the literature in at-least one homozygous individual affected with Mitochondrial DNA Depletion Syndrome - MPV17 Related (example: Samantha_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 36753038). ClinVar contains an entry for this variant (Variation ID: 1339192). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |