ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.391T>C (p.Tyr131His) (rs562847013)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188542 SCV000242160 uncertain significance not specified 2017-09-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the POLG gene. The Y131H variant has been published as a benign variant in an individual; however, no clinical information was provided (Gonzalez-Vioque et al., 2006). The Y131H variant subsequently has been reported in an individual with a clinical presentation suggestive of POLG deficiency; however, additional clinical information was not provided and information regarding parental testing was not available (Tang et al., 2011). The authors concluded that Y131H is an unclassified variant (Tang et al., 2011). The Y131H variant is observed in 12/14298 (0.08%) alleles from individuals of European Non-Finnish background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y131H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726559 SCV000345498 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing
Invitae RCV000469850 SCV000543878 uncertain significance Progressive sclerosing poliodystrophy 2020-01-05 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 131 of the POLG protein (p.Tyr131His). The tyrosine residue is weakly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs562847013, ExAC 0.08%). This variant has been observed in individuals with progressive external opthalmoplegia (PMID: 16401742) and with suspected POLG deficiency (PMID: 21880868). ClinVar contains an entry for this variant (Variation ID: 206492). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Undiagnosed Diseases Network,NIH RCV000578205 SCV000622173 uncertain significance Mitochondrial DNA depletion syndrome; Primary progressive multiple sclerosis 2016-01-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000726559 SCV000885996 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing The p.Tyr131His variant (rs562847013) has been reported as a polymorphism in an individual diagnosed with mitochondrial disease and as an unclassified variant in an individual whose features were suggestive of POLG deficiency; however, inheritance and specific clinical information were not reported for these cases (González-Vioque 2006 and Tang 2011). The p.Tyr131His variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.037% in the non-Finnish European population (identified in 34 out of 92,102 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 206492). The tyrosine at codon 131 is weakly conserved considering 12 species (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: tolerated, PolyPhen2: benign, MutationTaster: disease causing). Therefore, based on the available information, the clinical significance of the p.Tyr131His variant cannot be determined with certainty.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000469850 SCV000887004 likely benign Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.391T>C (NP_002684.1:p.Tyr131His) [GRCH38: NC_000015.10:g.89333364A>G] 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. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726559 SCV000892143 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001116622 SCV001274732 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252352 SCV001428104 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.