ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.695G>A (p.Arg232His)

gnomAD frequency: 0.00001  dbSNP: rs113994093
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412961 SCV000491139 pathogenic not provided 2023-10-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a reduction in DNA processivity and polymerase gamma holoenzyme steady state levels (Lee et al., 2010; Macao et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25585994, 23430834, 20301791, 18828154, 22237560, 23921535, 17088268, 26095671, 16896309, 18195151, 22000311, 27538604, 27475922, 26056153, 24508722, 32391929, 20513922)
Labcorp Genetics (formerly Invitae), Labcorp RCV003514301 SCV004296600 pathogenic Progressive sclerosing poliodystrophy 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 232 of the POLG protein (p.Arg232His). This variant is present in population databases (rs113994093, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16896309, 18195151, 18828154, 22000311, 25585994, 27538604, 28471437). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant POLG-related conditions (PMID: 23921535); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 21319). 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 80%. Experimental studies have shown that this missense change affects POLG function (PMID: 20513922, 26095671). This variant disrupts the p.Arg232 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 15689359), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020483 SCV000040920 not provided Mitochondrial disease no assertion provided literature only

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