Submissions for variant NM_002693.3(POLG):c.428C>T (p.Ala143Val)

gnomAD frequency: 0.00004  dbSNP: rs796052899

Total submissions: 8

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 Laboratory Services, 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 Center for Human Genetics Tuebingen	RCV000995420	SCV001149580	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758269	SCV001484248	pathogenic	Progressive sclerosing poliodystrophy	2024-06-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 143 of the POLG protein (p.Ala143Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive POLG-related conditions (PMID: 17452231, 19344718, 21880868, 29474836). ClinVar contains an entry for this variant (Variation ID: 206577). 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%. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	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.
MGZ Medical Genetics Center	RCV002288792	SCV002579555	likely pathogenic	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis	2021-11-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779176	SCV003800916	pathogenic	POLG-Related Spectrum Disorders	2023-01-18	criteria provided, single submitter	clinical testing	Variant summary: POLG c.428C>T (p.Ala143Val) results in a non-conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 168520 control chromosomes. c.428C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of POLG-Related Spectrum Disorders (example, Sarzi_2007, Amiot_2009, Tang_2011, Nuzhnyi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000758269	SCV004205848	pathogenic	Progressive sclerosing poliodystrophy	2024-03-07	criteria provided, single submitter	clinical testing