Submissions for variant NM_002693.3(POLG):c.2246T>C (p.Phe749Ser)

gnomAD frequency: 0.00024  dbSNP: rs202037973

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188572	SCV000242193	likely pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17538929, 21824913, 23446635, 32347949, 34777884, 21670405, 17280874, 21880868, 16545482, 18716558, 21953457, 19195941, 24642831, Alghtani_Article, 28206745, 35289132, 36510129, 38845467, 32391929, 17682973)
Eurofins Ntd Llc (ga)	RCV000188572	SCV000339752	uncertain significance	not provided	2016-02-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758416	SCV000956727	pathogenic	Progressive sclerosing poliodystrophy	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 749 of the POLG protein (p.Phe749Ser). This variant is present in population databases (rs202037973, gnomAD 0.07%). This missense change has been observed in individuals with Alpers syndrome, autosomal recessive progressive external ophthalmoplegia, and/or seizures (PMID: 16545482, 18716558, 21670405, 21880868, 28865037). ClinVar contains an entry for this variant (Variation ID: 206520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000758416	SCV001139680	pathogenic	Progressive sclerosing poliodystrophy	2019-05-28	criteria provided, single submitter	clinical testing
New York Genome Center	RCV004799198	SCV001441353	likely pathogenic	Progressive sclerosing poliodystrophy; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4b	2022-01-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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.
DASA	RCV001270867	SCV002318963	likely pathogenic	POLG-Related Spectrum Disorders	2022-03-25	criteria provided, single submitter	clinical testing	The c.2246T>C;p.(Phe749Ser) missense change has been observed in affected individual(s) PMID: 24642831; PMID: 21880868; PMID: 21670405)-PS4_moderate. The variant is present at low allele frequencies population databases (rs202037973 – gnomAD 0.0006368%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. The p.(Phe749Ser) was detected in trans with a pathogenic variant (PMID: 21880868; PMID: 21670405) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic
Ambry Genetics	RCV002514034	SCV003751409	likely pathogenic	Inborn genetic diseases	2021-08-12	criteria provided, single submitter	clinical testing	The c.2246T>C (p.F749S) alteration is located in exon 13 (coding exon 12) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 2246, causing the phenylalanine (F) at amino acid position 749 to be replaced by a serine (S). Based on the supporting evidence, this alteration is classified as likely pathogenic for autosomal recessive POLG-related mitochondrial disorders; however, its clinical significance for autosomal dominant progressive external ophthalmoplegia is unclear. Based on data from gnomAD, the C allele has an overall frequency of 0.01% (18/282674) total alleles studied. The highest observed frequency was 0.07% (17/24960) of African alleles. This alteration has been identified in the compound heterozygous state in individuals exhibiting a range a phenotypes associated with autosomal recessive POLG-related mitochondrial disorders (Milone, 2011; Nguyen, 2006; Tang, 2011; Zsurka, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001270867	SCV003922877	likely pathogenic	POLG-Related Spectrum Disorders	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: POLG c.2246T>C (p.Phe749Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251288 control chromosomes. c.2246T>C has been reported in the literature in multiple compound heterozygous individuals carrying additional pathogenic variants affected with clinical features of POLG-related disorders (examples: Tang_2011, Milone_2011, Zsurka_2008), including reduced mitochondrial enzyme activity (Zsurska_2008), and in Alpers syndrome (examples: Hikmat_2017, Nguyen_2006). These data indicate that the variant is very likely to be associated with disease. Two publications report predictive evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (examples: Euro_2011, Zsurska_2008). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=2), likely pathogenic (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003985755	SCV004118192	likely pathogenic	POLG-related disorder	2023-06-22	criteria provided, single submitter	clinical testing	The POLG c.2246T>C variant is predicted to result in the amino acid substitution p.Phe749Ser. This variant has previously been reported in the compound heterozygous state in patients who presented with POLG-associated disorders, including Alpers syndrome, progressive external ophthalmoplegia (PEO), and intractable seizures (Nguyen et al. 2006. PubMed ID: 16545482; Zsurka et al. 2008. PubMed ID: 18716558; Milone et al. 2011. PubMed ID: 21670405; Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89866654-A-G). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000758416	SCV004205873	pathogenic	Progressive sclerosing poliodystrophy	2024-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008114	SCV005633401	likely pathogenic	Progressive sclerosing poliodystrophy; 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	2024-05-16	criteria provided, single submitter	clinical testing