ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.2591A>G (p.Asn864Ser)

gnomAD frequency: 0.00001  dbSNP: rs121918050
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002513043 SCV003441697 pathogenic Progressive sclerosing poliodystrophy 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 864 of the POLG protein (p.Asn864Ser). This variant is present in population databases (rs121918050, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 12825077, 30634555, 32005694). 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: 13506). 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. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586006 SCV005076263 pathogenic Mitochondrial DNA depletion syndrome 2024-04-13 criteria provided, single submitter clinical testing Variant summary: POLG c.2591A>G (p.Asn864Ser) results in a conservative amino acid change located in the DNA polymerase gamma, palm domain (IPR047580) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.2591A>G has been reported in the literature as a biallelic genotype in individuals affected with features of AR-Mitochondrial DNA Depletion Syndrome - POLG Related (example, Van Goethem_2003, Lund_2015, Jou_2019, Bychkov_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function using the Saccharomyces Cerevisiae ortholog of human POLG (Stumpf_2010). The most pronounced variant effect results in significant decreases or total depletion of mtDNA, suggesting that mtDNA loss is characteristic of POLG-related disease. ClinVar contains an entry for this variant (Variation ID: 13506). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000014458 SCV000034709 pathogenic Mitochondrial DNA depletion syndrome 4b 2003-07-01 no assertion criteria provided literature only

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