Variant classification summary

NM_001126131.1:c.3436C>T

POLG · NP_001119603.1:p.(Arg1146Cys) · NM_001126131.1

GRCh37: chr15:89861818 G>A · GRCh38: chr15:89318587 G>A

Gene: POLG Transcript: NM_001126131.1

Final call

VUS

PP3 supporting BS1 strong

Variant details

Gene

POLG

Transcript

NM_001126131.1

Protein

NP_001119603.1:p.(Arg1146Cys)

gnomAD AF

0.00018742750445582368 (v2.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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%.

3

The variant is absent from gnomAD v4.1 and gnomAD-Canada.

4

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.

5

SpliceAI predicts no splicing impact (max delta score = 0.00).

6

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).

7

The variant has been observed once in the COSMIC somatic cancer database (COSV51525791).

8

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).

9

No de novo observations, segregation data, same-residue pathogenic comparators, or functional studies were identified for this specific variant in the available evidence.

10

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	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.
PS2	Not met	No de novo observation for this variant has been reported in any of the available evidence sources or publications.
PS3	N/A	PS3 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene.	cspec
PS4	N/A	PS4 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene.	cspec
PS5	N/A	Not included in the ONLY ASSESS list for this adjudication.
PM1	Not met	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.	cspec
PM2	Not met	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%.	gnomad_v2 cspec
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo observation (confirmed or assumed) for this variant has been reported in any available evidence source or publication.
PP1	Not met	No co-segregation data is available for this variant. Neither family studies nor segregation analysis has been reported in the literature or ClinVar.
PP2	N/A	PP2 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene.	cspec
PP3	Met	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.	revel cspec
PP4	Not met	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.
PP5	N/A	PP5 is designated as Not Applicable by the ClinGen Sequence Variant Interpretation VCEP Review Committee for this VCEP.	cspec
BA1	Not met	The maximum population allele frequency of 0.03508% (gnomAD v2.1 East Asian) is below the POLG VCEP BA1 threshold of >0.092%.	gnomad_v2 gnomad_v4 cspec
BS1	Met	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%.	gnomad_v2 cspec
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	N/A	BS3 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene.	cspec
BS4	Not met	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.
BP1	N/A	BP1 is designated as Not Applicable by the Mitochondrial Disease Nuclear and Mitochondrial VCEP for this gene.	cspec
BP2	Not met	No evidence of the variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant has been reported.
BP3	N/A	This is a single-nucleotide substitution variant, not an in-frame deletion or insertion. BP3 applies only to in-frame deletions/insertions in repetitive regions.
BP4	Not met	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.	revel cspec spliceai
BP5	Not met	No evidence has been identified of this variant being found in a case with an alternate molecular basis for disease.
BP6	N/A	BP6 is designated as Not Applicable by the ClinGen Sequence Variant Interpretation VCEP Review Committee for this VCEP.	cspec
BP7	N/A	This 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.

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