Submissions for variant NM_002437.5(MPV17):c.70+5G>A

gnomAD frequency: 0.00001  dbSNP: rs267607268

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331860	SCV004037766	pathogenic	Mitochondrial DNA depletion syndrome	2023-08-30	criteria provided, single submitter	clinical testing	Variant summary: MPV17 c.70+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the 5' canonical splicing donor site. One predicts the variant abolishes the 5 canonical splicing donor site. At least two publications report in vivo and in vitro experimental evidence that this variant affects normal mRNA splicing by skipping exon 2 and normal mRNA product of MPV17 is abolished (Navarro-Sastre_2008 and 2010). The variant allele was found at a frequency of 3.2e-05 in 31410 control chromosomes. c.70+5G>A has been reported in the literature at a homozygous state in two individuals affected with severe hepatopathy, polyneuropathy, neurological regression with Leukodystrophy, and other characteristic symptoms of mitochondrial diseases (example, Navarro-Sastre_2008 and 2010). These data indicate that the variant is very likely to be associated with MPV17 Related Mitochondrial DNA Depletion Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 20614188, 18329934). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003561306	SCV004292108	likely pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the MPV17 gene. It does not directly change the encoded amino acid sequence of the MPV17 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs267607268, gnomAD 0.007%). This variant has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 18329934). ClinVar contains an entry for this variant (Variation ID: 2581455). Studies have shown that this variant alters MPV17 gene expression (PMID: 18329934). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 18329934, 20614188). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.