rs113994099
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000268124.11(POLG):āc.2864A>Gā(p.Tyr955Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y955H) has been classified as Pathogenic.
Frequency
Consequence
ENST00000268124.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2864A>G | p.Tyr955Cys | missense_variant | 18/23 | ENST00000268124.11 | NP_002684.1 | |
POLGARF | NM_001406557.1 | c.*2136A>G | 3_prime_UTR_variant | 18/23 | NP_001393486.1 | |||
POLG | NM_001126131.2 | c.2864A>G | p.Tyr955Cys | missense_variant | 18/23 | NP_001119603.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2864A>G | p.Tyr955Cys | missense_variant | 18/23 | 1 | NM_002693.3 | ENSP00000268124 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461664Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727140
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2020 | Functional studies demonstrated in the absence of intrinsic proofreading activity, the Y955C variant was associated with increased error rate during DNA synthesis (Ponamarev et al., 2002; Estep et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32161153, 31521625, 30848931, 12210792, 15702133, 21880868, 23673011, 11431686, 28430993, 16595552, 24943079, 27987238, 21228000, 19010300, 12565911, 2067633, 2725645, 11897778, 15258572, 17310215, 17725985, 16940310, 16368709, 23811324, 21696159, 15351195, 31263856) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 06, 2020 | Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families. - |
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 08, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | POLG: PP1:Strong, PM2, PS4:Moderate, PP3, PS3:Supporting - |
Progressive sclerosing poliodystrophy Pathogenic:2
Pathogenic, 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.2864A>G (NP_002684.1:p.Tyr955Cys) [GRCH38: NC_000015.10:g.89320883T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. PM2:This variant is absent in key population databases. PM3:Detected in trans with a pathogenic variant for Mitochondrial DNA depletion syndrome 4A (Alpers type) which is a recessive disorder. PP1:This variant is co-segregated with Mitochondrial DNA depletion syndrome 4A (Alpers type) in multiple affected family members. PP4:Patient's phenotype or family history is highly specific for POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 955 of the POLG protein (p.Tyr955Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 11431686, 16595552, 31521625, 32161153). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13495). 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 expected to disrupt POLG protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial disease Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Wellcome Centre for Mitochondrial Research, Newcastle University | Apr 07, 2017 | - - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 2004 | - - |
Mitochondrial DNA depletion syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2023 | Variant summary: POLG c.2864A>G (p.Tyr955Cys) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family A, palm domain (IPR001098) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2864A>G has been reported in the literature in multiple heterozygous individuals affected with progressive external ophthalmoplegia with Mitochondrial DNA Depletion, autosomal dominant with evidence of familial co-segregation (e.g. Lamantea_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced mitochondrial bioenergetics with 10%-<30% of normal growth capability in vitro (e.g. Rahman_2022). The following publications have been ascertained in the context of this evaluation (PMID: 12210792, 35760101). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at