ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.2207A>G (p.Asn736Ser) (rs138457939)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188567 SCV000242187 likely benign not specified 2018-01-29 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.
Genetic Services Laboratory, University of Chicago RCV000188567 SCV000248556 uncertain significance not specified 2014-04-21 criteria provided, single submitter clinical testing
Invitae RCV000231376 SCV000287667 uncertain significance Progressive sclerosing poliodystrophy 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 736 of the POLG protein (p.Asn736Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs138457939, ExAC 0.1%). This variant has been observed in individuals affected with a spectrum of phenotypes suspected to be related to POLG-deficiency (PMID: 21654874, 21880868). ClinVar contains an entry for this variant (Variation ID: 206516). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000515256 SCV000611502 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2017-05-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000712791 SCV000700969 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000712791 SCV000843320 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000716683 SCV000847525 uncertain significance Seizures 2016-06-18 criteria provided, single submitter clinical testing The p.N736S variant (also known as c.2207A>G), located in coding exon 12 of the POLG gene, results from an A to G substitution at nucleotide position 2207. The asparagine at codon 736 is replaced by serine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs138457939. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.05% (7/12998) total alleles studied, having been observed in 0.11% (5/4400) African American alleles and 0.02% (2/8598) European American alleles. Allele frequency data for this nucleotide position is not currently available from the 1000 Genomes Project. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000231376 SCV000887295 benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.2207A>G (NP_002684.1:p.Asn736Ser) [GRCH38: NC_000015.10:g.89323462T>C] 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 Clinical Services Laboratory,Illumina RCV001119421 SCV001277820 uncertain significance POLG-Related Spectrum Disorders 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252353 SCV001428105 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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