ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.3643+2T>C

dbSNP: rs1335880349
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV001526407 SCV001736745 pathogenic Mitochondrial disease 2021-05-06 reviewed by expert panel curation The c.3643+2T>C variant in POLG has been reported in trans with other another pathogenic variant (p.Trp784Ser) in a child with Alpers syndrome (PM3; PMID: 20691285). This variant was found at 0.00001% allele frequency in gnomAD and no homozygotes reported (PM2). This variant affects a donor splice site causing complete skipping of exon 22, resulting in disruptions in mRNA (PVS1; PMID 20691285). In summary, this variant meets criteria to be classified as pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2, PM3.
Eurofins Ntd Llc (ga) RCV000734043 SCV000862154 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001037377 SCV001200788 pathogenic Progressive sclerosing poliodystrophy 2023-11-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 of the POLG gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with POLG-related conditions (PMID: 19500334, 20691285). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 597808). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 22 and introduces a new termination codon (PMID: 20691285). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002507306 SCV002815856 pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b 2021-10-28 criteria provided, single submitter clinical testing

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