Submissions for variant NM_002693.3(POLG):c.391T>C (p.Tyr131His)

gnomAD frequency: 0.00027  dbSNP: rs562847013

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726559	SCV000242160	uncertain significance	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Reported as an unclassified variant in an individual with a clinical presentation suggestive of POLG deficiency; additional clinical information was not provided and information regarding parental testing was not available (PMID: 21880868); Reported as a benign variant in an individual with multiple mtDNA deletions; no clinical information was provided (PMID: 16401742); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21880868, 16401742)
Eurofins Ntd Llc (ga)	RCV000726559	SCV000345498	uncertain significance	not provided	2017-12-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469850	SCV000543878	uncertain significance	Progressive sclerosing poliodystrophy	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 131 of the POLG protein (p.Tyr131His). This variant is present in population databases (rs562847013, gnomAD 0.04%). This missense change has been observed in individual(s) with mitochondrial myopathy and/or progressive external opthalmoplegia (PMID: 2504279, 16401742, 21880868). ClinVar contains an entry for this variant (Variation ID: 206492). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLG protein function with a negative predictive value of 95%. 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 Center for Human Genetics Tuebingen	RCV000726559	SCV000892143	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	POLG: PM2
Illumina Laboratory Services, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000726559	SCV001716245	uncertain significance	not provided	2019-10-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000726559	SCV001879843	uncertain significance	not provided	2022-09-27	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.
Ambry Genetics	RCV002321761	SCV002626299	uncertain significance	Inborn genetic diseases	2024-03-29	criteria provided, single submitter	clinical testing	The c.391T>C (p.Y131H) alteration is located in exon 2 (coding exon 1) of the POLG gene. This alteration results from a T to C substitution at nucleotide position 391, causing the tyrosine (Y) at amino acid position 131 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.02% (43/217988) total alleles studied. The highest observed frequency was 0.037% (35/94380) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000726559	SCV003809196	uncertain significance	not provided	2021-12-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985750	SCV004782848	uncertain significance	POLG-related disorder	2024-01-30	criteria provided, single submitter	clinical testing	The POLG c.391T>C variant is predicted to result in the amino acid substitution p.Tyr131His. This variant has been reported in two individuals with mitochondrial disease; however, no evidence was provided to determine its pathogenicity (González-Vioque et al. 2006. PubMed ID: 16401742; Tang et al. 2011. PubMed ID: 21880868). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993876	SCV004813942	uncertain significance	not specified	2024-02-12	criteria provided, single submitter	clinical testing	Variant summary: POLG c.391T>C (p.Tyr131His) results in a conservative amino acid change located in the DNA mitochondrial polymerase, exonuclease domain (IPR041336) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 186608 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the gnomAD database. c.391T>C has been reported in the literature in the heterozygous state in an individual with clinical features suggestive of POLG deficiency and as a polymorphism in an individual diagnosed with mitochondrial disease who had multiple mtDNA deletions, however no further genotype information was provided (Gonzalez-Vioque_2006, Tang_2011). These reports do not provide unequivocal conclusions about association of the variant with POLG-Related Spectrum Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16401742, 21880868). ClinVar contains an entry for this variant (Variation ID: 206492). Based on the evidence outlined above, the variant was classified as uncertain significance.
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