About POLG
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
POLG c.3436C>T, p.(Arg1146Cys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen POLG VCEP v1.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PP3Supporting
PP3 · supporting
The REVEL in silico predictor score of 0.915 exceeds the VCEP-specified threshold of >0.75 for PP3 at Supporting strength, indicating multiple lines of computational evidence support a deleterious effect.
Benign criteria applied · 1
BS1Strong
BS1 · strong
The variant is present in gnomAD v2.1 at an overall allele frequency of 0.01874% (53/282,776 alleles) with a maximum subpopulation frequency of 0.03508% in East Asians, which exceeds the POLG VCEP BS1 threshold of >0.0092%.
Recorded classification: Uncertain significance
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PP3 supporting, BS1 strong; combination = 1 supporting + 1 strong benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000187428; MAF= 0.01874%, 53/282776 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000350807; MAF= 0.03508%, 7/19954 alleles, homozygotes = 0); grpmax FAF= 0.00018972.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
9 reported laboratory submissions
8 Uncertain significance · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLG, a mitochondrial DNA polymerase, is infrequently altered in cancers. Mutations in POLG are associated with inherited mitochondrial disorders, inc
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV51525791, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen POLG VCEP v1.0.0, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001126131.1:c.3436C>T (p.Arg1146Cys) is a missense variant in exon 21 of POLG, encoding the catalytic subunit of mitochondrial DNA polymerase gamma.
This variant is present in gnomAD v2.1 at an overall allele frequency of 0.01874% (53/282,776 alleles, 0 homozygotes), with the highest subpopulation frequency of 0.03508% in the East Asian population, exceeding the VCEP BS1 threshold of >0.0092%.
The variant is absent from gnomAD v4.1 and gnomAD-Canada.
The REVEL in silico prediction score of 0.915 exceeds the VCEP threshold of >0.75 for PP3 at Supporting strength, indicating computational evidence of a deleterious effect.
SpliceAI predicts no splicing impact (max delta score = 0.00).
This variant has been reported in ClinVar (VariationID: 21313) as a Variant of Uncertain Significance by 8 clinical laboratories and as Benign by 1 clinical laboratory (review status: criteria provided, single submitter).
The variant has been observed once in the COSMIC somatic cancer database (COSV51525791).
Amino acid position 1146 is not located within any of the POLG functional domains specified by the VCEP (TPP binding site, heterodimer interface, heterotetramer interface, or phosphorylation loop).
No de novo observations, segregation data, same-residue pathogenic comparators, or functional studies were identified for this specific variant in the available evidence.
Applying the VCEP framework: BS1 (Strong benign) is met based on population frequency exceeding the gene-specific threshold; PP3 (Supporting pathogenic) is met based on REVEL score >0.75. No other criteria are met. The strong benign criterion outweighs the single supporting pathogenic criterion.
No criteria match.
Met · 2
PP3 SupportingThe REVEL in silico predictor score of 0.915 exceeds the VCEP-specified threshold of >0.75 for PP3 at Supporting strength, indicating multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.915. VCEP PP3 threshold: REVEL >0.75 (Supporting). BayesDel score = 0.513 (supportive but not independently applied per VCEP). SpliceAI max delta = 0.00 (no splicing impact).
Sources
revelcspec ↗
BS1 StrongThe variant is present in gnomAD v2.1 at an overall allele frequency of 0.01874% (53/282,776 alleles) with a maximum subpopulation frequency of 0.03508% in East Asians, which exceeds the POLG VCEP BS1 threshold of >0.0092%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: overall AF=0.01874% (53/282
- 776 alleles
- 0 homozygotes)
- grpmax FAF=0.00018972
- East Asian AF=0.03508%. VCEP BS1 threshold: >0.000092 (>0.0092%).
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 1146 resulting in the same amino acid change (p.Arg1146Cys) that has been established as pathogenic. The variant c.3436C>T is the only observed nucleotide change producing p.Arg1146Cys. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change producing p.Arg1146Cys identified in ClinVar or literature.
Still missing
- Pathogenic comparator variant with same amino acid change but different nucleotide change not found.
PS2 No de novo observation for this variant has been reported in any of the available evidence sources or publications. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified.
Still missing
- De novo status not assessed in any available study.
PM1 Amino acid position 1146 (Arg1146) is not located within any of the POLG functional domains specified by the VCEP: TPP binding site, alpha-beta heterodimer interface, alpha2-beta2 heterotetramer interface, or phosphorylation loop region. Details ▾Hide ▴
Evidence considered
- Residue 1146 is not in any VCEP-specified POLG functional domain (TPP binding: 118-292
- heterodimer interface: 160-213
- heterotetramer interface: 88-300
- phosphorylation loop: 287-316).
Sources
PM2 The variant is present in gnomAD v2.1 at an allele frequency of 0.01874% (53/282,776 alleles), which exceeds the POLG VCEP PM2 threshold of <0.00092%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.0001874 (0.01874%)
- 53/282
- 776 alleles
- 0 homozygotes. VCEP PM2 threshold: <0.0000092 (<0.00092%).
Sources
PM5 No pathogenic missense variants at amino acid position 1146 other than p.Arg1146Cys were identified in ClinVar or the literature. Without a same-residue pathogenic comparator, PM5 cannot be applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 candidates. No pathogenic missense comparator at residue 1146.
Still missing
- No same-residue pathogenic missense comparator found.
Sources
pm5_candidates
PM6 No de novo observation (confirmed or assumed) for this variant has been reported in any available evidence source or publication. Details ▾Hide ▴
Evidence considered
- No de novo evidence identified in ClinVar or literature.
Still missing
- De novo status not assessed in any available study.
PP1 No co-segregation data is available for this variant. Neither family studies nor segregation analysis has been reported in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- Family segregation studies not available.
PP4 No patient phenotype data is available for this adjudication. The VCEP PP4 rules require specific clinical and biochemical findings (mtDNA depletion, multiple mtDNA deletions, COX-negative fibers, or specific POLG-spectrum disorder manifestations) that cannot be evaluated without case-level phenotype information. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available to evaluate against VCEP PP4 criteria (mtDNA depletion ≤20% or multiple deletions
- COX-negative fibers
- urinary ethylmalonic acid with specific symptom clusters).
Still missing
- Patient phenotype and biochemical data not provided for this adjudication.
BA1 The maximum population allele frequency of 0.03508% (gnomAD v2.1 East Asian) is below the POLG VCEP BA1 threshold of >0.092%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.01874% overall
- max subpopulation East Asian AF=0.03508%. gnomAD v4.1: absent. VCEP BA1 threshold: >0.00092 (>0.092%).
Sources
BS2 No homozygous individuals are observed in gnomAD (0 homozygotes across 282,776 alleles in v2.1; absent in v4.1). There is no evidence of a healthy adult individual homozygous for this variant, which is required for BS2 at Strong strength under the VCEP. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes in 282
- 776 alleles. gnomAD v4.1: variant absent. No published report of a healthy adult homozygote.
Sources
BS4 No segregation data is available for this variant. Neither family-based segregation analysis nor reports of lack of segregation in affected family members have been identified. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data identified.
Still missing
- Family segregation studies not available.
BP2 No evidence of the variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
- No phase information or co-occurrence data with pathogenic variants identified.
Still missing
- Phase determination with other POLG variants not available.
BP4 The REVEL score of 0.915 far exceeds the VCEP BP4 threshold of <0.15. Multiple lines of computational evidence suggest a deleterious effect rather than a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.915 (VCEP BP4 threshold: <0.15). BayesDel = 0.513. SpliceAI max delta = 0.00 (no splicing impact
- but REVEL alone exceeds BP4 threshold).
Sources
BP5 No evidence has been identified of this variant being found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis reported for carriers of this variant.
Still missing
- Alternate molecular basis data not available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.3436C>T, p.Arg1146Cys), not a null variant (nonsense, frameshift, or canonical splice site). The variant does not meet the PVS1 decision tree criteria for loss-of-function prediction. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- not eligible for PVS1 per ClinGen SVI PVS1 framework (PMC6185798).
Sources
pvs1_gene_contextpvs1_variant_assessment
PS3 VCEPPS3 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene. Details ▾Hide ▴
PS4 VCEPPS4 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene. Details ▾Hide ▴
PP2 VCEPPP2 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene. Details ▾Hide ▴
PP5 VCEPPP5 is designated as Not Applicable by the ClinGen Sequence Variant Interpretation VCEP Review Committee for this VCEP. Details ▾Hide ▴
BS3 VCEPBS3 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene. Details ▾Hide ▴
BP1 VCEPBP1 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene. Details ▾Hide ▴
BP3 N/AThis is a single-nucleotide substitution variant, not an in-frame deletion or insertion. BP3 applies only to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
Evidence considered
- Variant type is substitution.
BP6 VCEPBP6 is designated as Not Applicable by the ClinGen Sequence Variant Interpretation VCEP Review Committee for this VCEP. Details ▾Hide ▴
BP7 N/AThis is a missense variant (c.3436C>T, p.Arg1146Cys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg1146Cys)
- not synonymous.
PS5 N/ANot included in the ONLY ASSESS list for this adjudication. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- POLG
- Transcript
- NM_001126131.1
- Coding (HGVS c.)
- NM_001126131.1:c.3436C>T
- Protein (HGVS p.)
- NP_001119603.1:p.(Arg1146Cys)
- GRCh38
- chr15:89318587 G>A
- GRCh37
- chr15:89861818 G>A
- ClinVar
- 21313
- COSMIC
- COSV51525791
Gene diagram
Every interpreted variant in POLG, mapped onto the exon structure of NM_001126131.1. Select a row to find it on the plot.
POLGNM_001126131.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLG
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
53 / 282,776 alleles
AF 0.000187 · 0 homozygotes · FAF 0.00019
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v2.1
AF 0.00019 · 53 / 282,776 alleles · 0 hom · FAF 0.00019
| East Asian7 / 19,954 | 0.00035 |
| European (non-Finnish)36 / 129,110 | 0.00028 |
| South Asian5 / 30,616 | 0.00016 |
| Remaining individuals1 / 7,226 | 0.00014 |
| Admixed American3 / 35,438 | 8.5e-05 |
| African/African American1 / 24,956 | 4e-05 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000187428; MAF= 0.01874%, 53/282776 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000350807; MAF= 0.03508%, 7/19954 alleles, homozygotes = 0); grpmax FAF= 0.00018972.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.915
- BayesDel
- 0.513
How the predictions were used
PP3 SupportingThe REVEL in silico predictor score of 0.915 exceeds the VCEP-specified threshold of >0.75 for PP3 at Supporting strength, indicating multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.915. VCEP PP3 threshold: REVEL >0.75 (Supporting). BayesDel score = 0.513 (supportive but not independently applied per VCEP). SpliceAI max delta = 0.00 (no splicing impact).
Sources
revelcspec ↗
BP4 The REVEL score of 0.915 far exceeds the VCEP BP4 threshold of <0.15. Multiple lines of computational evidence suggest a deleterious effect rather than a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.915 (VCEP BP4 threshold: <0.15). BayesDel = 0.513. SpliceAI max delta = 0.00 (no splicing impact
- but REVEL alone exceeds BP4 threshold).
Sources
BP7 N/AThis is a missense variant (c.3436C>T, p.Arg1146Cys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg1146Cys)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.915. BayesDel score = 0.512792.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 16401742 ↗Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population.González-Vioque E et al. · 2006No paper-specific finding is recorded.
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PMID 20843780 ↗Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing.Wang W et al. · 2011No paper-specific finding is recorded.
-
PMID 21880868 ↗Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum.Tang S et al. · 2011No paper-specific finding is recorded.
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PMID 25462018 ↗Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae.Baruffini E et al. · 2015No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 30838265 ↗Dystonia in a Patient with Autosomal-Dominant Progressive External Ophthalmoplegia Type 1 Caused by Mutation in the POLG Gene.Rossi M et al. · 2017No paper-specific finding is recorded.
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PMID 32613234 ↗The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.Zhao Y et al. · 2020No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
8 Uncertain significance · 1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637587
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/21313/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-89861818-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-89318587-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001126131.1%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/POLG/R1146C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=120406613
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000187428; MAF= 0.01874%, 53/282776 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000350807; MAF= 0.03508%, 7/19954 alleles, homozygotes = 0); grpmax FAF= 0.00018972.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 21313)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.915. BayesDel score = 0.512792.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLG, a mitochondrial DNA polymerase, is infrequently altered in cancers. Mutations in POLG are associated with inherited mitochondrial disorders, inc
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51525791, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.