15-89327004-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_002693.3(POLG):​c.1493A>C​(p.Lys498Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,614,102 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.95
Variant links:
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
MIR6766 (HGNC:49941): (microRNA 6766) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.1493A>C p.Lys498Thr missense_variant Exon 8 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.1493A>C p.Lys498Thr missense_variant Exon 8 of 23 1 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251488
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000217
AC:
317
AN:
1461886
Hom.:
2
Cov.:
34
AF XY:
0.000205
AC XY:
149
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000279
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:2
Sep 16, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: POLG c.1493A>C (p.Lys498Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in POLG causing POLG-Related Spectrum Disorders, allowing no conclusion about variant significance. c.1493A>C has been reported in the literature in individuals affected with Alpers syndrome or Cerebellar Ataxia (Hikmat_2017, Coutelier_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29482223, 28471437, 28865037, 34690748). ClinVar contains an entry for this variant (Variation ID: 206597). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 12, 2017
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:2
Aug 29, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2_moderate, PM3_supporting -

Dec 05, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in a patient with Alpers syndrome who also harbors an likely disease-causing variant in the POLG gene (PMID: 28471437); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28865037, 28471437) -

Progressive sclerosing poliodystrophy Uncertain:2
Dec 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 498 of the POLG protein (p.Lys498Thr). This variant is present in population databases (rs769637557, gnomAD 0.008%). This missense change has been observed in individual(s) with Alpers syndrome (PMID: 28471437). ClinVar contains an entry for this variant (Variation ID: 206597). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. 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. -

Oct 01, 2018
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The NM_002693.2:c.1493A>C (NP_002684.1:p.Lys498Thr) [GRCH38: NC_000015.10:g.89327004T>G] 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. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). 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. -

Inborn genetic diseases Uncertain:1
Jul 20, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Hikmat, 2017a; Hikmat, 2017b Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

POLG-related disorder Uncertain:1
Mar 20, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The POLG c.1493A>C variant is predicted to result in the amino acid substitution p.Lys498Thr. This variant was reported with a second POLG variant in an individual with Alpers syndrome (Supp. Table 1 in Hikmat et al 2017. PubMed ID: 28865037). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;D
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Uncertain
0.74
D
MutationAssessor
Benign
1.6
L;L
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Pathogenic
0.77
Sift
Benign
0.048
D;D
Sift4G
Uncertain
0.055
T;T
Polyphen
1.0
D;D
Vest4
0.66
MVP
0.86
MPC
0.72
ClinPred
0.59
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.50
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs769637557; hg19: chr15-89870235; API