rs1085307741
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_002693.3(POLG):c.3573G>T(p.Lys1191Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1191R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002693.3 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 | UniProt |
---|---|---|---|---|---|---|---|
POLG | NM_002693.3 | c.3573G>T | p.Lys1191Asn | missense_variant | 22/23 | ENST00000268124.11 | |
POLGARF | NM_001406557.1 | c.*2845G>T | 3_prime_UTR_variant | 22/23 | |||
POLG | NM_001126131.2 | c.3573G>T | p.Lys1191Asn | missense_variant | 22/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLG | ENST00000268124.11 | c.3573G>T | p.Lys1191Asn | missense_variant | 22/23 | 1 | NM_002693.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
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.3573G>T (NP_002684.1:p.Lys1191Asn) [GRCH38: NC_000015.10:g.89317446C>A] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:16621917 . 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. 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. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. 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 | Invitae | Dec 02, 2022 | ClinVar contains an entry for this variant (Variation ID: 426681). This missense change has been observed in individual(s) with autosomal recessive POLG-related disorders (PMID: 16621917, 19538466, 30423451). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1191 of the POLG protein (p.Lys1191Asn). 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. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 07, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30423451, 16621917, 21038416, 21880868, 19538466, 24508722) - |
Mitochondrial disease Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | May 06, 2021 | The c.3573G>T (p.K1191N) variant in POLG is absent in population databases (PM2). Computational prediction tool Revel score 0.876 (PP3 met - Revel score > 0.75). This variant has been seen in 3 cases in the compound heterozygote state: in two cases, with Ala467Thr presenting with Alpers syndrome, and one with c.752C>T (p.Thr251Ile) / c.1760 C>T (p.Pro587Leu) presenting with CPEO spectrum (PM3_strong met; PMID: 16621917; PMID: 21880868; PMID: 19538466). In summary, this variant is characterized as a likely pathogenic variant for primary mitochondrial disease inherited in an autosomal recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: PM2, PM3_strong, PP3. - |
POLG-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 02, 2023 | The POLG c.3573G>T variant is predicted to result in the amino acid substitution p.Lys1191Asn. This variant has been reported in the compound heterozygous state with the pathogenic variant p.Ala467Thr or a pathogenic complex allele p.[Thr251Ile;Pro587Leu] in individuals with POLG-related disorders (Horvath et al. 2006. PubMed ID: 16621917; Müller-Höcker et al. 2011. PubMed ID: 19538466; Piekutowska-Abramczuk et al. 2018. PubMed ID: 30423451; Table S2, Kierdaszuk et al. 2021. PubMed ID: 33396418). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as likely pathogenic by the ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/426681/). We interpret this variant as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at