ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000188572 SCV000339752 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000188572 SCV000843322 likely pathogenic not provided 2020-03-23 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
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.
Invitae RCV000758416 SCV000956727 uncertain significance Progressive sclerosing poliodystrophy 2020-07-08 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.
Mendelics RCV000758416 SCV001139680 pathogenic Progressive sclerosing poliodystrophy 2019-05-28 criteria provided, single submitter clinical testing
New York Genome Center RCV001263312 SCV001441353 likely pathogenic Seizures; Intellectual disability 2020-03-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001270867 SCV001451643 likely pathogenic POLG-Related Spectrum Disorders 2019-04-26 criteria provided, single submitter clinical testing The POLG c.2246T>C (p.Phe749Ser) variant is a missense variant that has been reported in four studies, in which it is found in a compound heterozygous state in a total of six individuals, including in three with POLG deficiency, in one with autosomal recessive POLG-related disorders, in one with Alpers syndrome, and in one with some features of the Alpers-Huttenlocher syndrome (Nguyen et al. 2006; Zsurka et al. 2008; Milone et al. 2011; Tang et al. 2011). The p.Phe749Ser variant was absent from 100 control subjects and is reported at a frequency of 0.000681 in the African population of the Genome Aggregation Database. The p.Phe749Ser variant demonstrated reduced mitochondrial DNA copy numbers in patient blood and tissue samples (Zsurka et al. 2008). Muscle biopsies from the Alpers-Huttenlocher syndrome patient revealed large mtDNA deletions, however, the mitochondrial impairment in the muscle tissue could not be explained solely by deletions (Zsurka et al. 2008). The phe749 residue is in the linker region suggested to be involved in protein–protein interactions but is not critical for catalytic function of the enzyme (Euro et al. 2011). Based on the collective evidence, the p.Phe749Ser variant is classified as likely pathogenic for POLG-related spectrum disorders.

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