ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.428C>T (p.Ala143Val) (rs796052899)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000758269 SCV000886917 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.428C>T (NP_002684.1:p.Ala143Val) [GRCH38: NC_000015.10:g.89333327G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. 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. 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.
Illumina Clinical Services Laboratory,Illumina RCV000779176 SCV000915697 pathogenic POLG-Related Spectrum Disorders 2018-10-22 criteria provided, single submitter clinical testing The POLG c.428C>T (p.Ala143Val) variant has been reported in at least three studies and is found in at least nine probands including eight in a compound heterozygous state, and one in a heterozygous state (Sarzi et al. 2007; Tang et al. 2011; Tchikviladze et al. 2015). An additional proband was found to have the p.Ala143Val variant in a homozygous state with two other variants in POLG in a heterozygous state, one of which reportedly contributes to disease and the other a modifier of disease (Amiot et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.000133 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage, so the variant is presumed to be rare. Based on the evidence the p.Ala143Val variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000995420 SCV001149580 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Invitae RCV000758269 SCV001484248 uncertain significance Progressive sclerosing poliodystrophy 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 143 of the POLG protein (p.Ala143Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 21880868, 17452231, 25118206, 19344718). ClinVar contains an entry for this variant (Variation ID: 206577). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000995420 SCV001879844 likely pathogenic not provided 2020-12-15 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

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