POLD1 c.868G>A, p.Val290Met
NM_002691.4:c.868G>A
COSMIC ID: COSM10438584, COSM10438585
Variant of Uncertain Significance (VUS)
NM_002691.4:c.868G>A (p.V290M) in POLD1 is classified as a Variant of Uncertain Significance. The variant is extremely rare (PM2) and computational evidence supports benign effect (BP4), but insufficient functional, segregation, de novo, or case-control data precludes a definitive classification.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
POLD1
Transcript
NM_002691.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000019.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_002691.2 | Alternative | 27 exons | Forward |
| NM_002691.1 | Alternative | 27 exons | Forward |
| NM_002691.3 | Alternative | 27 exons | Forward |
Variant Details
HGVS Notation
NM_002691.4:c.868G>A
Protein Change
V290M
Location
Exon 8
(Exon 8 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 290 in gene POLD1
Alternate Identifiers
COSM10438584, COSM10438585
Variant interpretation based on transcript NM_002691.4
Genome Browser
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HGVS InputNM_002691:c.868G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00248%
Rare
Highest in Population
African/African American
0.00821%
Rare
Global: 0.00248%
African/African American: 0.00821%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 201364Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00248%, 5/201364 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00821%, 1/12176 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 290 in gene POLD1
Functional Summary
The POLD1 V290M variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.267
0.267
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
mutationtaster: D
Benign:
CADD: 3.80metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: a missense change (V290M), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant does not introduce a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant at residue V290. Therefore, this criterion is not applied at Not Applied strength because there is no known pathogenic variant resulting in V290M.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied at Not Applied strength because de novo status has not been established.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional characterization available. Therefore, this criterion is not applied at Not Applied strength because functional study data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control data or enrichment in patient cohorts. Therefore, this criterion is not applied at Not Applied strength because prevalence in affected individuals has not been demonstrated.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: insufficient domain annotation or hotspot information. Therefore, this criterion is not applied at Not Applied strength because placement in a mutational hotspot or critical domain is not established.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: absent or extremely rare in control populations (gnomAD MAF=0.00248%). Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on trans configuration with other variants. Therefore, this criterion is not applied at Not Applied strength because trans evidence is lacking.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: this is a missense change without alteration of protein length. Therefore, this criterion is not applied at Not Applied strength because protein length is unchanged.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense changes reported at residue V290. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variants at this residue are known.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo family data. Therefore, this criterion is not applied at Not Applied strength because de novo status is unconfirmed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied at Not Applied strength because family segregation evidence is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: gene-specific missense constraint data not provided. Therefore, this criterion is not applied at Not Applied strength because gene-level missense constraint has not been established.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational predictions are predominantly benign. Therefore, this criterion is not applied at Not Applied strength because in silico data do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity is not available.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: no authoritative pathogenic reports. Therefore, this criterion is not applied at Not Applied strength because no reputable source lists this variant as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF is 0.00248%, far below a high-frequency threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not sufficiently high.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: frequency is below expected thresholds. Therefore, this criterion is not applied at Not Applied strength because allele frequency is not excessive.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder". The evidence for this variant shows: population database health status is unknown. Therefore, this criterion is not applied at Not Applied strength because observation in healthy individuals with confirmed phenotype is lacking.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied at Not Applied strength because functional assays are not available.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength because family segregation evidence is absent.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: disease mechanism for POLD1 involves missense changes in some contexts. Therefore, this criterion is not applied at Not Applied strength because missense is a known mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans configuration. Therefore, this criterion is not applied at Not Applied strength because phasing information is lacking.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: this is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because the variant is not an in-frame indel in a repetitive region.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: in silico tools predominantly benign predictions and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational data support a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no cases with an alternate molecular diagnosis. Therefore, this criterion is not applied at Not Applied strength because no such case context exists.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: conflicting ClinVar submissions (mostly VUS). Therefore, this criterion is not applied at Not Applied strength because a clear benign report is not established.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: a nonsynonymous missense change. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.