ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.3667A>G (p.Ile1223Val) (rs148786642)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000548544 SCV000630157 uncertain significance Progressive sclerosing poliodystrophy 2020-08-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1223 of the POLG protein (p.Ile1223Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs148786642, ExAC 0.009%). This variant has been reported as heterozygous in an individual affected 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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing

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