Submissions for variant NM_002693.3(POLG):c.3671T>C (p.Ile1224Thr)

gnomAD frequency: 0.00002  dbSNP: rs779072487

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522166	SCV000617281	uncertain significance	not provided	2018-03-21	criteria provided, single submitter	clinical testing	The I1224T variant in the POLG gene has been reported previously in an individual with a clinical diagnosis of Alpers syndrome, however, a second variant was not detected in the POLG gene (Tang et al., 2011). The I1224T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The I1224T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I1224T as a variant of uncertain significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758337	SCV000887002	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3671T>C (NP_002684.1:p.Ile1224Thr) [GRCH38: NC_000015.10:g.89316800A>G] variant in FANCI gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on FANCI structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758337	SCV000964447	uncertain significance	Progressive sclerosing poliodystrophy	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1224 of the POLG protein (p.Ile1224Thr). This variant is present in population databases (rs779072487, gnomAD 0.004%). This missense change has been observed in individual(s) with Alpers syndrome (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 449313). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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.