Submissions for variant NM_002693.3(POLG):c.3098C>T (p.Ala1033Val)

gnomAD frequency: 0.00032  dbSNP: rs551708243

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000710186	SCV000242133	likely benign	not provided	2020-10-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21880868, 30290626)
Eurofins Ntd Llc (ga)	RCV000710186	SCV000342437	uncertain significance	not provided	2017-10-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710186	SCV000614719	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551001	SCV000630140	likely benign	Progressive sclerosing poliodystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000551001	SCV000886980	uncertain significance	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.3098C>T (NP_002684.1:p.Ala1033Val) [GRCH38: NC_000015.10:g.89319234G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000765239	SCV000896475	uncertain significance	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
Illumina Laboratory Services, Illumina	RCV001121338	SCV001279932	uncertain significance	POLG-Related Spectrum Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV001332169	SCV001524397	uncertain significance	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1	2020-09-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000710186	SCV001715128	uncertain significance	not provided	2020-07-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000710186	SCV003809207	uncertain significance	not provided	2022-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732759	SCV005364371	uncertain significance	POLG-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The POLG c.3098C>T variant is predicted to result in the amino acid substitution p.Ala1033Val. This variant has been reported in the compound heterozygous state along with a second variant in this gene in a individual with hypotonia, low set ears, and bilateral clubfeet (AlJabri et al. 2018. PubMed ID: 30290626) and found in the heterozygous condition another individual with encephalopathy, seizure, and abnormal MRI (Table S2, Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.