rs562847013
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_002693.3(POLG):c.391T>C(p.Tyr131His) variant causes a missense change. The variant allele was found at a frequency of 0.000308 in 1,575,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y131Y) has been classified as Likely benign.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.391T>C | p.Tyr131His | missense_variant | 2/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.446T>C | p.Leu149Pro | missense_variant | 2/23 | ||
POLG | NM_001126131.2 | c.391T>C | p.Tyr131His | missense_variant | 2/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.391T>C | p.Tyr131His | missense_variant | 2/23 | 1 | NM_002693.3 | P1 | |
POLGARF | ENST00000706918.1 | c.446T>C | p.Leu149Pro | missense_variant | 1/2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152230Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000198 AC: 37AN: 186608Hom.: 0 AF XY: 0.000216 AC XY: 22AN XY: 102040
GnomAD4 exome AF: 0.000314 AC: 447AN: 1423502Hom.: 0 Cov.: 32 AF XY: 0.000317 AC XY: 224AN XY: 705748
GnomAD4 genome ? AF: 0.000249 AC: 38AN: 152348Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74492
ClinVar
Submissions by phenotype
not provided Uncertain:7
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 27, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2023 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 20, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 10, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | POLG: PM2 - |
Progressive sclerosing poliodystrophy Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 01, 2018 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2024 | 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. - |
Mitochondrial DNA depletion syndrome;C0751964:Primary progressive multiple sclerosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Jan 28, 2016 | - - |
POLG-Related Spectrum Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 21, 2018 | The p.Y131H variant (also known as c.391T>C), located in coding exon 1 of the POLG gene, results from a T to C substitution at nucleotide position 391. The tyrosine at codon 131 is replaced by histidine, an amino acid with similar properties. This alteration was identified in the heterozygous state in one individual with features suggestive of POLG, however no specific clinical information was available and the variant remained unclassified (Tang S et al. J. Med. Genet., 2011 Oct;48:669-81). This amino acid position is not 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 alteration remains unclear. - |
POLG-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2024 | 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. - |
Intellectual disability Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at