Submissions for variant NM_002693.3(POLG):c.3667A>G (p.Ile1223Val)

gnomAD frequency: 0.00004  dbSNP: rs148786642

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000548544	SCV000630157	uncertain significance	Progressive sclerosing poliodystrophy	2022-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1223 of the POLG protein (p.Ile1223Val). This variant is present in population databases (rs148786642, gnomAD 0.01%). This missense change has been observed in individual(s) with headaches, exercise intolerance, muscle weakness, easy fatigability, ptosis, gastrointestinal reflux, delayed gastric emptying, constipation, vomiting, low plasma carnitine, and CPK abnormalities (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 458718). 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 not expected to disrupt POLG protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000548544	SCV000887304	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3667A>G (NP_002684.1:p.Ile1223Val) [GRCH38: NC_000015.10:g.89316804T>C] variant in FANCI gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the FANCI structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Fulgent Genetics, Fulgent Genetics	RCV000765232	SCV000896468	uncertain significance	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001591204	SCV001822624	uncertain significance	not provided	2022-10-14	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in an individual with a clinical presentation suggestive of POLG deficiency; however, information regarding parental testing was not available (Tang et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21880868)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848933	SCV002104879	uncertain significance	Hereditary spastic paraplegia	2018-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001591204	SCV002541291	uncertain significance	not provided	2021-06-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479152	SCV004223281	uncertain significance	not specified	2023-11-03	criteria provided, single submitter	clinical testing	Variant summary: POLG c.3667A>G (p.Ile1223Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251370 control chromosomes (gnomAD). c.3667A>G has been reported in the literature in individuals who had epileptic panel test performed, however authors classified the variant as uncertain significance. (example: Li_2022). This report does not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35478072). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=5) and likely benign(n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.