Submissions for variant NM_002693.3(POLG):c.1386G>A (p.Ser462=)

gnomAD frequency: 0.00061  dbSNP: rs62640034

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127560	SCV000171137	benign	not specified	2014-04-17	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)	RCV000725999	SCV000341136	uncertain significance	not provided	2016-11-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000402563	SCV000394292	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.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000758496	SCV000887213	likely benign	Progressive sclerosing poliodystrophy	2018-10-01	criteria provided, single submitter	clinical testing	The NM_002693.2:c.1386G>A (NP_002684.1:p.Ser462=) [GRCH38: NC_000015.10:g.89327214C>T] variant in POLG gene is interpretated to be a Likely 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). BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP7:The variant is silent with non predicted splice impact. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758496	SCV001005860	likely benign	Progressive sclerosing poliodystrophy	2024-01-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847758	SCV002105548	likely benign	Hereditary spastic paraplegia	2021-06-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985733	SCV004775161	likely benign	POLG-related disorder	2020-04-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).