Submissions for variant NM_002693.3(POLG):c.911T>G (p.Leu304Arg)

gnomAD frequency: 0.00004  dbSNP: rs121918044

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188648	SCV000242271	pathogenic	not provided	2020-06-10	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: 24288107, 20601675, 16639411, 21880868, 16368709, 22006280, 11431686, 30634555, 31521625, 32161153, 31589614, 33469851)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000188648	SCV000610658	likely pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000014444	SCV000680343	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2017-11-08	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000626287	SCV000746945	pathogenic	Progressive sclerosing poliodystrophy	2017-12-18	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000626287	SCV000886922	likely pathogenic	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.911T>G (NP_002684.1:p.Leu304Arg) [GRCH38: NC_000015.10:g.89329055A>C] variant in POLG gene is interpretated to be a Likely Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:11431686 . This variant meets the following evidence codes reported in the ACMG-guideline. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. 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 Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762954	SCV000893386	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	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000626287	SCV001212784	pathogenic	Progressive sclerosing poliodystrophy	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 304 of the POLG protein (p.Leu304Arg). This variant is present in population databases (rs121918044, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 11431686, 16639411, 21880868, 22006280, 24288107). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13497). 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: 20601675, 26095671). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000014444	SCV001426445	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266602	SCV001444778	pathogenic	Inborn genetic diseases	2019-02-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000626287	SCV001524402	pathogenic	Progressive sclerosing poliodystrophy	2024-03-23	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813984	SCV001755354	pathogenic	Abnormality of the mitochondrion	2021-07-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000188648	SCV001762164	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000188648	SCV002019461	pathogenic	not provided	2019-10-03	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000626287	SCV002583594	likely pathogenic	Progressive sclerosing poliodystrophy	2022-10-17	criteria provided, single submitter	clinical testing	The variant c.911 T>G (p.Leu304Arg) is present in compound heterozygous state with c.368 T>G (p.Val123Gly) in POLG gene. The four month old patient had two episodes of pneumonia and Acute Respiratory Distress Syndrome. Other clinical features observed were severe sepsis, shock, reduced IgG and increased levels of CK, Ferritin, SGOT and FGF-21. This variant has been present in 0.036% in gnomAD and 0.0074% in ExAc. The c.911 variant was observed 'in trans' with c.368 variant as both segregated separately in mother and father of the proband. This variant has been reported previously PMID: 32567010. Based on segregation studies and the clinical features, this variant is classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000014444	SCV002600899	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2022-10-17	criteria provided, single submitter	clinical testing	A Hetrozygous variation in exon 4 of the POLG gene that results in the aminoacid substitution of Arginine for Leucine at codon 304 was detected.The observed variant c.911T>G (p.Leu304Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across species.In summary, the variant meets our criteria to be classified as pathogenic.
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV003387722	SCV003920800	pathogenic	POLG-related disorder	2023-04-27	criteria provided, single submitter	research
OMIM	RCV000014444	SCV000034694	pathogenic	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2001-07-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003387722	SCV005362679	pathogenic	POLG-related disorder	2024-03-15	no assertion criteria provided	clinical testing	The POLG c.911T>G variant is predicted to result in the amino acid substitution p.Leu304Arg. This variant has been reported in the compound heterozygous or homozygous states in patients with a POLG-related disorder, such as Alpers-Huttenlocher syndrome, autosomal recessive progressive external ophthalmoplegia, or sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) (Spiegler et al. 2011. PubMed ID: 22006280; Szczepanowska et al. 2010. PubMed ID: 20601675). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.