rs773994204
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The ENST00000268124.11(POLG):c.1904C>T(p.Pro635Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,608,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P635P) has been classified as Likely benign.
Frequency
Consequence
ENST00000268124.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.1904C>T | p.Pro635Leu | missense_variant | 10/23 | ENST00000268124.11 | NP_002684.1 | |
POLGARF | NM_001406557.1 | c.*1176C>T | 3_prime_UTR_variant | 10/23 | NP_001393486.1 | |||
POLG | NM_001126131.2 | c.1904C>T | p.Pro635Leu | missense_variant | 10/23 | NP_001119603.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.1904C>T | p.Pro635Leu | missense_variant | 10/23 | 1 | NM_002693.3 | ENSP00000268124 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 247042Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133958
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1456692Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 724890
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74290
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 10, 2024 | Reported in trans with a benign variant in POLG in an individual with colorectal cancer; no further clinical information was provided (PMID: 25850945); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25850945) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 17, 2023 | BP4 - |
Progressive sclerosing poliodystrophy Uncertain:2
Uncertain significance, 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.1904C>T (NP_002684.1:p.Pro635Leu) [GRCH38: NC_000015.10:g.89325495G>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 31, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 635 of the POLG protein (p.Pro635Leu). This variant is present in population databases (rs773994204, gnomAD 0.003%). 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: 206503). 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. 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. - |
POLG-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 11, 2024 | The POLG c.1904C>T variant is predicted to result in the amino acid substitution p.Pro635Leu. To our knowledge, this variant has not been reported in individuals with POLG-related disease. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at