POLD1 c.2185G>A, p.Glu729Lys
NM_002691.4:c.2185G>A
COSMIC ID: COSM6325609
Variant of Uncertain Significance (VUS)
This POLD1 E729K missense variant is extremely rare (PM2 Moderate) and computational evidence predicts no impact (BP4 Supporting). No other criteria could be applied or were unevaluable due to missing data. The evidence is insufficient to classify as pathogenic or benign; thus it remains a Variant of Uncertain Significance.
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.2185G>A
Protein Change
E729K
Location
Exon 18
(Exon 18 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 729 in gene POLD1
Alternate Identifiers
COSM6325609
Variant interpretation based on transcript NM_002691.4
Genome Browser
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HGVS InputNM_002691:c.2185G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0164%
Low Frequency
Highest in Population
Remaining individuals
0.0836%
Common
Global: 0.0164%
Remaining individuals: 0.0836%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281022Alt: 46Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0164%, 46/281022 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0836%, 6/7178 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
3 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 (5 clinical laboratories) and as Likely benign (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 729 in gene POLD1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.234
0.234
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: 5.06polyphen_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 (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (E729K), not a null variant. Therefore, this criterion is not applied because the variant does not meet the definition of a null LoF variant.
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 regardless of nucleotide change". The evidence for this variant shows: no other pathogenic variant has been reported at residue E729. Therefore, this criterion is not applied because there is no prior pathogenic variant with the same amino acid change.
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 occurrence has been documented and parental testing data are unavailable. Therefore, this criterion is not applied due to lack of de novo confirmation.
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 studies have been performed. Therefore, this criterion is not applied due to absence of functional data.
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 or familial prevalence data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied due to lack of statistical association data.
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: E729 is not within a known hotspot or critical functional domain lacking benign variation. Therefore, this criterion is not applied because the variant does not lie in a recognized mutational hotspot.
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: present in gnomAD at MAF=0.0164% (46/281022 alleles) with no homozygotes, below the 0.1% threshold. 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 reports of this variant in trans with a pathogenic POLD1 variant. Therefore, this criterion is not applied due to absence of trans observation data.
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 change in protein length. Therefore, this criterion is not applied because there is no alteration of protein length.
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 have been reported at residue E729. Therefore, this criterion is not applied because there is no known pathogenic variant at this codon.
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 assumption data are available. Therefore, this criterion is not applied due to lack of any de novo evidence.
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 are available. Therefore, this criterion is not applied due to absence of family segregation information.
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: POLD1 does not have clear evidence of low benign missense variation rate or a predominance of pathogenic missense mechanism. Therefore, this criterion is not applied because gene-specific constraints do not support it.
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 or gene product". The evidence for this variant shows: in silico tools (CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, REVEL=0.23, SpliceAI=0) predominantly predict benign impact. Therefore, this criterion is not applied because computational evidence does not support 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 context was provided. Therefore, this criterion is not applied due to lack of phenotype information.
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: ClinVar submissions are conflicting (VUS and Likely Benign). Therefore, this criterion is not applied because no unequivocally pathogenic report exists without evidence.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0.0164%, far below the >5% threshold. Therefore, this criterion is not applied because allele frequency is not excessively 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 low (0.0164%) relative to expected for a dominant condition. Therefore, this criterion is not applied because the frequency does not exceed disease prevalence expectations.
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 (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance". The evidence for this variant shows: no documented observations in confirmed healthy individuals. Therefore, this criterion is not applied due to lack of healthy individual data.
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 such functional studies exist. Therefore, this criterion is not applied due to absence of functional assay data.
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 analysis has been performed. Therefore, this criterion is not applied due to absence of segregation information.
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". The evidence for this variant shows: POLD1 disease mechanisms include pathogenic missense variants. Therefore, this criterion is not applied because missense is a known mechanism of disease in POLD1.
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 observations of this variant in cis or trans with pathogenic POLD1 variants. Therefore, this criterion is not applied due to lack of such observations.
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: it is a missense change, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied because it does not meet the indel context.
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: CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI predict benign; REVEL=0.23; SpliceAI=0. Therefore, this criterion is applied at Supporting strength because computational evidence consistently predicts no functional impact.
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 reported with an alternative molecular basis. Therefore, this criterion is not applied due to absence of such case data.
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: ClinVar submissions include conflicting assertions and some likely benign calls with accessible evidence. Therefore, this criterion is not applied because no single benign assertion without evidence is present.
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: it is a nonsynonymous (missense) variant. Therefore, this criterion is not applied because the variant is not synonymous.