ClinVar Miner

Submissions for variant NM_002693.3(POLG):c.1720C>T (p.Arg574Trp)

gnomAD frequency: 0.00001  dbSNP: rs774474723
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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 RCV002007520 SCV002230556 pathogenic Progressive sclerosing poliodystrophy 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 574 of the POLG protein (p.Arg574Trp). This variant is present in population databases (rs774474723, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive POLG-related conditions (PMID: 16621917, 16896309, 19125351). 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: 1452045). 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: 20601675, 20883824, 27987238). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003322908 SCV004028168 pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing Published functional studies found this variant is associated with significantly impaired POLG enzyme activity (Szczepanowska K and Foury F., 2010; Kasahara T et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28815208, 27987238, 22537151, 25852747, 20883824, 16621917, 19125351, 32391929, 22342071, 20185557, 25476511, 16896309, 22237560, 20601675)
Baylor Genetics RCV002007520 SCV004205871 pathogenic Progressive sclerosing poliodystrophy 2023-11-18 criteria provided, single submitter clinical testing

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