ClinVar Genomic variation as it relates to human health
NM_002691.4(POLD1):c.203G>A (p.Gly68Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002691.4(POLD1):c.203G>A (p.Gly68Glu)
Variation ID: 239267 Accession: VCV000239267.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.33 19: 50399371 (GRCh38) [ NCBI UCSC ] 19: 50902628 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Sep 28, 2017 May 12, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002691.4:c.203G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002682.2:p.Gly68Glu missense NM_001256849.1:c.203G>A NP_001243778.1:p.Gly68Glu missense NM_001308632.1:c.203G>A NP_001295561.1:p.Gly68Glu missense NR_046402.2:n.248G>A non-coding transcript variant NC_000019.10:g.50399371G>A NC_000019.9:g.50902628G>A NG_033800.1:g.20049G>A LRG_785:g.20049G>A LRG_785t1:c.203G>A LRG_785p1:p.Gly68Glu LRG_785t2:c.203G>A LRG_785p2:p.Gly68Glu - Protein change
- G68E
- Other names
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- Canonical SPDI
- NC_000019.10:50399370:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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POLD1 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4875 | 4924 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000233715.14 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 8, 2016 | RCV000477990.9 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 20, 2023 | RCV000657137.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000765468.2 | |
POLD1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jul 20, 2023 | RCV004532876.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 10
Mandibular hypoplasia-deafness-progeroid syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896759.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Dec 08, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712718.2
First in ClinVar: Apr 09, 2018 Last updated: Jul 06, 2018 |
Comment:
The p.Gly68Glu variant in POLD1 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/66138 European chr omosomes … (more)
The p.Gly68Glu variant in POLD1 has not been previously reported in individuals with colorectal cancer. This variant has been identified in 3/66138 European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs144707871). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. This var iant is located in the first base of the exon (which is part of the 3? splice re gion) but computational tools do not suggest a significant impact on splicing. H owever, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Gly68Glu variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Aug 04, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601899.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 01, 2022 |
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Uncertain significance
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 10
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012369.2
First in ClinVar: Nov 11, 2021 Last updated: Dec 24, 2022 |
Comment:
The POLD1 c.203G>A (p.Gly68Glu) missense change has a maximum subpopulation frequency of 0.0071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/19-50902628-G-A). Four of six in silico tools predict a … (more)
The POLD1 c.203G>A (p.Gly68Glu) missense change has a maximum subpopulation frequency of 0.0071% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/19-50902628-G-A). Four of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. In addition, algorithms that predict the impact of sequence changes on splicing indicate that this change is unlikely to significantly impact splicing. To our knowledge, this variant has not been reported in the literature in individuals with POLD1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. (less)
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Uncertain significance
(Apr 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799576.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The POLD1 c.203G>A; p.Gly68Glu variant (rs144707871), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239267). This … (more)
The POLD1 c.203G>A; p.Gly68Glu variant (rs144707871), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 239267). This variant is found in the general population with an overall allele frequency of 0.003% (8/250932 alleles) in the Genome Aggregation Database. The glycine at codon 68 is moderately conserved, but computational analyses predict that this variant is neutral (REVEL: 0.107). This variant is not located in the exonuclease domain (Palles 2013), and gene-disease association has not been established for variants outside of the exonuclease domain (Seifert 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. References: Palles C et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013 Feb;45(2):136-44. PMID: 23263490 Seifert BA et al. Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework. Genet Med. 2019 Jul;21(7):1507-1516. PMID: 30523343 (less)
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Uncertain significance
(Mar 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000570788.6
First in ClinVar: Apr 29, 2017 Last updated: Mar 26, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
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Uncertain significance
(Jul 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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POLD1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120489.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The POLD1 c.203G>A variant is predicted to result in the amino acid substitution p.Gly68Glu. To our knowledge, this variant has not been reported in the … (more)
The POLD1 c.203G>A variant is predicted to result in the amino acid substitution p.Gly68Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50902628-G-A). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/239267/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, susceptibility to, 10
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000287548.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 68 of the POLD1 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 68 of the POLD1 protein (p.Gly68Glu). This variant is present in population databases (rs144707871, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 239267). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jul 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004140549.5
First in ClinVar: Nov 20, 2023 Last updated: May 12, 2024 |
Comment:
POLD1: BP4
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs144707871 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.