POLD1 c.16C>T, p.Arg6Trp
NM_002691.4:c.16C>T
Variant of Uncertain Significance (VUS)
This POLD1 R6W variant remains classified as a Variant of Uncertain Significance because two Moderate pathogenic criteria (PM2, PM5) are present alongside a single Supporting benign criterion (BP4), with insufficient additional evidence to reach a definitive pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PM5
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.16C>T
Protein Change
R6W
Location
Exon 2
(Exon 2 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 6: R6P, R6Q
Variant interpretation based on transcript NM_002691.4
Genome Browser
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HGVS InputNM_002691:c.16C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00149%
Rare
Highest in Population
South Asian
0.00675%
Rare
Global: 0.00149%
South Asian: 0.00675%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 268100Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00149%, 4/268100 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00675%, 2/29620 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 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 Likely benign (1 clinical laboratories) and as Uncertain significance (2 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
ClinVar reports other pathogenic variants at position 6: R6P, R6Q
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.08
0.08
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
Benign:
CADD: 4.00polyphen_prediction: benignmetasvm: 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'. The evidence for this variant shows it is a missense change rather than a null variant. Therefore, this criterion is not applied because the variant does not meet the rule for PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant but different nucleotide change'. The evidence for this variant shows no known pathogenic variant results in the same R6W amino acid change. Therefore, this criterion is not applied because the variant does not meet the rule for PS1.
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'. There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied because no de novo evidence is available.
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. Therefore, this criterion is not applied because functional 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'. There are no case-control or affected individual data for this variant. Therefore, this criterion is not applied because prevalence data in affected cases are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or well-established functional domain without benign variation'. The evidence for this variant shows it occurs outside any known hotspot or critical functional domain. Therefore, this criterion is not applied because the residue is not in a defined hotspot or domain.
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 a MAF of 0.00149% in gnomAD, meeting the extremely low frequency threshold. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. There are no data on trans configuration with another pathogenic allele. Therefore, this criterion is not applied because trans data are unavailable.
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 it is a missense substitution without length change. Therefore, this criterion is not applied because there is no alteration in protein length.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen'. The evidence for this variant shows R6 has been previously altered by a different pathogenic missense variant. Therefore, this criterion is applied at Moderate strength because the residue is known to harbor pathogenic changes.
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'. There are no data on assumed de novo occurrence. Therefore, this criterion is not applied because de novo status without confirmation is not established.
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'. There are no co-segregation data available. Therefore, this criterion is not applied because 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 and gene context does not clearly meet this rule. Therefore, this criterion is not applied due to insufficient supporting evidence.
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'. The computational evidence for this variant (REVEL=0.08, benign predictions) does not support a deleterious impact. Therefore, this criterion is not applied because in silico tools predict no damaging effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history is highly specific for a disease with a single genetic etiology'. No clinical phenotype data are provided. Therefore, this criterion is not applied 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 without accessible evidence'. ClinVar submissions do not report this variant as pathogenic. Therefore, this criterion is not applied because there is no reputable pathogenic report.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is >5% in population databases'. The variant MAF of 0.00149% is well below this threshold. Therefore, this criterion is not applied because the allele frequency is not high enough.
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 variant frequency is extremely low and does not exceed expected frequency. Therefore, this criterion is not applied because population frequency is not excessive.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. There are no data on healthy adult observations. Therefore, this criterion is not applied because healthy individual data are unavailable.
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'. There are no functional studies available. Therefore, this criterion is not applied because functional data are lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. There are no segregation data. Therefore, this criterion is not applied because segregation analysis is not available.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only loss of function causes disease'. POLD1 pathogenic variants are often missense in specific domains, not strictly loss of function. Therefore, this criterion is not applied.
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'. There are no data on phase. Therefore, this criterion is not applied because cis/trans configuration is unknown.
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 variant is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows a REVEL score of 0.08 (below threshold), benign predictions by CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, and minimal splicing impact per SpliceAI. Therefore, this criterion is applied at Supporting strength because in silico 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'. No such case information is available. Therefore, this criterion is not applied because alternate molecular diagnoses are not reported.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without accessible evidence'. ClinVar submissions include likely benign but underlying evidence is accessible. Therefore, this criterion is not applied.
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 variant is a missense substitution, not synonymous. Therefore, this criterion is not applied.