rs769827124
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5
The NM_002693.3(POLG):c.2419C>T(p.Arg807Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000026 in 1,613,856 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R807H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002693.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.2419C>T | p.Arg807Cys | missense_variant | 14/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*1691C>T | 3_prime_UTR_variant | 14/23 | |||
POLG | NM_001126131.2 | c.2419C>T | p.Arg807Cys | missense_variant | 14/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.2419C>T | p.Arg807Cys | missense_variant | 14/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250946Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135710
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461664Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727116
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
ClinVar
Submissions by phenotype
Progressive sclerosing poliodystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 807 of the POLG protein (p.Arg807Cys). This variant is present in population databases (rs769827124, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive POLG-related disorders (PMID: 16919951, 21357833, 28471437). ClinVar contains an entry for this variant (Variation ID: 279982). 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%. Experimental studies have shown that this missense change affects POLG function (PMID: 20185557). This variant disrupts the p.Arg807 amino acid residue in POLG. Other variant(s) that disrupt this residue have been observed in individuals with POLG-related conditions (PMID: 14635118, 21880868, 28471437), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
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.2419C>T (NP_002684.1:p.Arg807Cys) [GRCH38: NC_000015.10:g.89322749G>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16919951 ; 21550804 . 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21880868, 21550804, 16919951, 21357833, 20185557, 28471437, 29655203, 30423451, 33671400, 34179544, 33511646, 30936349, 34052969, 33600046) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | POLG: PM1, PM2, PM3, PM5, PP3, PS3:Supporting - |
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, Cologne University | Sep 30, 2020 | - - |
neonatal seizures Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jun 15, 2017 | present with homozygous ALDH7A1 pathogenic variant - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at