Submissions for variant NM_002693.3(POLG):c.970C>T (p.Pro324Ser)

dbSNP: rs2307437

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127555	SCV000171132	benign	not specified	2013-11-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Eurofins Ntd Llc (ga)	RCV000710190	SCV000341137	uncertain significance	not provided	2017-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468571	SCV000543875	likely benign	Progressive sclerosing poliodystrophy	2024-01-29	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710190	SCV000614738	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000468571	SCV000887106	benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.970C>T (NP_002684.1:p.Pro324Ser) [GRCH38: NC_000015.10:g.89328996G>A] variant in POLG gene is interpretated to be a Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BS1:The minor allele frequency of this allele is high for Mitochondrial DNA depletion syndrome 4A (Alpers type). 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. Based on the evidence criteria codes applied, the variant is suggested to be Benign.
Illumina Laboratory Services, Illumina	RCV001121509	SCV001280134	uncertain significance	POLG-Related Spectrum Disorders	2018-01-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000710190	SCV001716242	uncertain significance	not provided	2020-01-17	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000710190	SCV002051739	uncertain significance	not provided	2021-01-04	criteria provided, single submitter	clinical testing	No ACMG evidence could be applied applied
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847613	SCV002104893	uncertain significance	Hereditary spastic paraplegia	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371780	SCV002692661	uncertain significance	Inborn genetic diseases	2022-06-21	criteria provided, single submitter	clinical testing	Unlikely to be causative of AD POLG-related progressive external ophthalmoplegia. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000710190	SCV003809211	uncertain significance	not provided	2019-08-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710190	SCV004137641	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	POLG: BP4
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000710190	SCV001743087	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000710190	SCV001927806	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000127555	SCV001975034	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732552	SCV005356804	uncertain significance	POLG-related disorder	2024-07-26	no assertion criteria provided	clinical testing	The POLG c.970C>T variant is predicted to result in the amino acid substitution p.Pro324Ser. This variant has been reported in the heterozygous state in individuals with suspected POLG-deficiency and interpreted as uncertain significance (Tang et al. 2018. PubMed ID: 21880868). This variant is reported in 0.059% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.