ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.3218C>T (p.Pro1073Leu)

gnomAD frequency: 0.00002  dbSNP: rs267606959
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188673 SCV000242297 pathogenic not provided 2020-02-07 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31271879, 20883824, 23921535, 25914719, 20142534, 21880868)
Undiagnosed Diseases Network, NIH RCV000014470 SCV000837701 pathogenic Progressive sclerosing poliodystrophy 2018-01-03 criteria provided, single submitter clinical testing This variant has been reported in mulitple individuals with this Alpers phenotype (MIM 203700) in the literature. There is also one paper with data from yeast model (PMID:20883824).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000014470 SCV000886987 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.3218C>T (NP_002684.1:p.Pro1073Leu) [GRCH38: NC_000015.10:g.89318986G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Invitae RCV000014470 SCV000936270 pathogenic Progressive sclerosing poliodystrophy 2024-01-23 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1073 of the POLG protein (p.Pro1073Leu). This variant is present in population databases (rs267606959, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Alpers syndrome (PMID: 20142534, 20883824, 21880868, 25914719). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13516). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 20883824, 25914719). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000014470 SCV001524398 pathogenic Progressive sclerosing poliodystrophy 2020-01-29 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
MGZ Medical Genetics Center RCV000014470 SCV002579549 pathogenic Progressive sclerosing poliodystrophy 2021-11-16 criteria provided, single submitter clinical testing
OMIM RCV000014470 SCV000034721 pathogenic Progressive sclerosing poliodystrophy 2010-02-01 no assertion criteria provided literature only
OMIM RCV000014471 SCV000034722 pathogenic Mitochondrial DNA depletion syndrome 4b 2010-02-01 no assertion criteria provided literature only

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