rs748777396
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_002693.3(POLG):c.2596C>T(p.Arg866Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000255 in 1,608,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R866Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_002693.3 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2596C>T | p.Arg866Trp | missense_variant, splice_region_variant | 16/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1868C>T | splice_region_variant, 3_prime_UTR_variant | 16/23 | |||
POLG | NM_001126131.2 | c.2596C>T | p.Arg866Trp | missense_variant, splice_region_variant | 16/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2596C>T | p.Arg866Trp | missense_variant, splice_region_variant | 16/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251350Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135866
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1455956Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 724692
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74332
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | May 19, 2023 | 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 damaging. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 08, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2018 | The p.R866W variant (also known as c.2596C>T), located in coding exon 15 of the POLG gene, results from a C to T substitution at nucleotide position 2596. The arginine at codon 866 is replaced by tryptophan, an amino acid with dissimilar properties. In one study, this alteration was detected in 2/796 Japanese individuals with bipolar disorder and in 1/767 controls (Kasahara T et al. Psychiatry Clin. Neurosci., 2017 Aug;71:518-529). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 866 of the POLG protein (p.Arg866Trp). This variant is present in population databases (rs748777396, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 502515). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at