Submissions for variant NM_002693.3(POLG):c.2740A>C (p.Thr914Pro)

gnomAD frequency: 0.00008  dbSNP: rs139590686

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000321917	SCV000329630	pathogenic	not provided	2022-10-26	criteria provided, single submitter	clinical testing	Accounts for approximately 3% of disease-causing alleles and has been identified in patients with autosomal recessive POLG-related disorders, including Alpers syndrome and mitochondrial spinocerebellar ataxia and epilepsy (MSCAE) (Wong et al. 2008; Horvath et al. 2006; Taanman et al. 2009; Hinnell et al. 2012); Published functional studies demonstrate a damaging effect (Roos et al., 2013); 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: 16545482, 24642831, 20138553, 18487244, 30021052, 32042919, 23446635, 18828154, 16621917, 21357833, 18546365, 21956653, 16639411, 19578034, 23084792, 23446645, 21282586, 20843780, 27450679, 28471437, 30167885, 31425757, 25160553, 23921535, 21880868, 31980526)
Illumina Laboratory Services, Illumina	RCV000306622	SCV000394273	pathogenic	POLG-Related Spectrum Disorders	2017-04-27	criteria provided, single submitter	clinical testing	The POLG c.2740A>C (p.Thr914Pro) missense variant is well documented in the literature as one of the five most common pathogenic variants, that together, account for approximately 60% of disease alleles in patients with autosomal recessive POLG-related spectrum disorders. Across a selection of the available literature, the p.Thr914Pro variant has been identified in at least ten patients in a compound heterozygous state (Nguyen et al. 2006; Wong et al. 2008; Roos et al. 2013; Horvarth et al. 2013; Rouzier et al. 2014). The variant was also identified in a heterozygous state in an asymptomatic daughter of an affected individual (Roos et al. 2013). The variant was absent from 864 control chromosomes but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Thr914Pro variant is classified as pathogenic for POLG-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000633543	SCV000754789	pathogenic	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 914 of the POLG protein (p.Thr914Pro). This variant is present in population databases (rs139590686, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive adult onset progressive external ophthalmoplegia in a single family (PMID: 23446645). This variant has also been reported, along with a second, rare POLG variant in several individuals affected with a POLG-related disorder (PMID: 16621917, 21956653, 18487244, 21880868, 23921535, 20843780, 21357833, 21282586) including several individuals affected with Alpers syndrome (PMID: 16545482, 16639411, 18546365, 18828154, 23446635, 24642831, 27450679). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279961). 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 expected to disrupt POLG protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POLG function (PMID: 18828154, 23446635). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000321917	SCV000856717	pathogenic	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000633543	SCV000886910	pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.2740A>C (NP_002684.1:p.Thr914Pro) [GRCH38: NC_000015.10:g.89321007T>G] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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.
Baylor Genetics	RCV001004600	SCV001163770	pathogenic	Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4b		criteria provided, single submitter	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001848045	SCV002106311	likely pathogenic	Tip-toe gait	2021-10-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000321917	SCV002770699	pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with autosomal recessive POLG-related disorders and appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study shows this variant impairs DNA binding affinity and DNA polymerase activity compared to wild-type (PMID: 23446635). 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.
Fulgent Genetics, Fulgent Genetics	RCV002494810	SCV002794658	pathogenic	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	2021-11-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000633543	SCV004205846	pathogenic	Progressive sclerosing poliodystrophy	2023-10-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985765	SCV004750311	pathogenic	POLG-related disorder	2023-11-27	criteria provided, single submitter	clinical testing	The POLG c.2740A>C variant is predicted to result in the amino acid substitution p.Thr914Pro. This variant has been reported to be pathogenic for POLG-related disorders (Horvath et al. 2006. PubMed ID: 16621917; Wong et al. 2008. PubMed ID: 18546365; Tang et al. 2011. PubMed ID: 21880868; Hedberg-Oldfors et al. 2020. PubMed ID: 32042919). The majority of affected patients who carry this variant harbor a second pathogenic variant on the opposite allele (in trans), resulting in autosomal recessive disease. At least one patient, who presented with progressive external ophthalmoplegia (PEO), carried this variant in the heterozygous state alone (Wong et al. 2008. PubMed ID: 18546365). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-89864238-T-G). This variant is interpreted as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000321917	SCV000802082	pathogenic	not provided	2016-03-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000321917	SCV001742744	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000321917	SCV001800108	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000321917	SCV001969171	likely pathogenic	not provided		no assertion criteria provided	clinical testing