ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2246T>C (p.Phe749Ser) (rs202037973)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000188572 SCV000843322 likely pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000188572 SCV000339752 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000188572 SCV000242193 likely pathogenic not provided 2016-10-25 criteria provided, single submitter clinical testing The F749S variant in the POLG gene has been previously reported in association with autosomal recessive POLG-related disorders, including Alpers syndrome, intractable epilepsy, and optic atrophy in patients who harbored a second variant in the POLG gene (Nguyen et al., 2006; Zsurka et al., 2008; Tang et al., 2011; Milone et al., 2011). However, these studies did not specify if parents were tested to confirm the presence of these variants in the compound heterozygous state in these affected individuals. The F749S variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F749S 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. The F749S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000758416 SCV000956727 uncertain significance Progressive sclerosing poliodystrophy 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 749 of the POLG protein (p.Phe749Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs202037973, ExAC 0.07%). This variant has been observed in in combination with other POLG variants in individuals affected with autosomal recessive progressive external ophthalmoplegia, Alpers syndrome, or seizures (PMID: 21670405, 16545482, 21880868, 18716558). ClinVar contains an entry for this variant (Variation ID: 206520). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000758416 SCV000887114 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2246T>C (NP_002684.1:p.Phe749Ser) [GRCH38: NC_000015.10:g.89323423A>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16545482 ; 21880868 . This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.

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