ClinVar Genomic variation as it relates to human health
NM_002691.4(POLD1):c.1809CTC[1] (p.Ser605del)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002691.4(POLD1):c.1809CTC[1] (p.Ser605del)
Variation ID: 60775 Accession: VCV000060775.20
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 19q13.33 19: 50408818-50408820 (GRCh38) [ NCBI UCSC ] 19: 50912075-50912077 (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 14, 2015 May 1, 2024 Dec 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002691.4:c.1809CTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002682.2:p.Ser605del inframe deletion NM_002691.4:c.1812_1814del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001256849.1:c.1809CTC[1] NP_001243778.1:p.Ser605del inframe deletion NM_001256849.1:c.1812_1814del inframe deletion NM_001308632.1:c.1887CTC[1] NP_001295561.1:p.Ser631del inframe deletion NM_002691.3:c.1812_1814del NR_046402.2:n.1854CTC[1] non-coding transcript variant NC_000019.10:g.50408818CTC[1] NC_000019.9:g.50912075CTC[1] NG_033800.1:g.29496CTC[1] LRG_785:g.29496CTC[1] LRG_785t1:c.1809CTC[1] LRG_785p1:p.Ser605del LRG_785t2:c.1887CTC[1] LRG_785p2:p.Ser631del - Protein change
- S605del, S631del
- Other names
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- Canonical SPDI
- NC_000019.10:50408817:CTCCTC:CTC
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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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 20, 2022 | RCV000054542.33 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 1, 2017 | RCV000484962.5 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2017 | RCV000567311.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 26, 2019 | RCV001052191.7 | |
POLD1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV004537238.1 |
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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Pathogenic
(Jan 09, 2017)
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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: SCV000568849.4
First in ClinVar: Apr 27, 2017 Last updated: Dec 15, 2018 |
Comment:
The c.1812_1814delCTC variant in the POLD1 gene is a recurrent pathogenic variant which has been reported several times in association with MDPL (Weedon et al., … (more)
The c.1812_1814delCTC variant in the POLD1 gene is a recurrent pathogenic variant which has been reported several times in association with MDPL (Weedon et al., 2013; Lessel et al., 2015; Reinier et al., 2015). This variant results in an in-frame deletion of a single Serine residue, denoted p.Ser605del. The c.1812_1814delCTC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid residue removed by this variant is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1812_1814delCTC as a pathogenic variant. (less)
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Pathogenic
(Oct 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Mandibular hypoplasia-deafness-progeroid syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764837.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Talipes (present) , Sensorineural hearing loss disorder (present) , Lipodystrophy (present) , Muscular dystrophy (present) , Diabetes mellitus (present) , Polyneuropathy (present) , Hypogonadism (present) … (more)
Talipes (present) , Sensorineural hearing loss disorder (present) , Lipodystrophy (present) , Muscular dystrophy (present) , Diabetes mellitus (present) , Polyneuropathy (present) , Hypogonadism (present) , Hypertriglyceridemia (present) , Hyperkeratosis (present) (less)
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Pathogenic
(Apr 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mandibular hypoplasia-deafness-progeroid syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807609.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong
Number of individuals with the variant: 1
Clinical Features:
Joint stiffness (present) , Small hand (present) , Alopecia (present) , Camptodactyly (present) , Dry skin (present) , Microtia (present) , Short palm (present) , … (more)
Joint stiffness (present) , Small hand (present) , Alopecia (present) , Camptodactyly (present) , Dry skin (present) , Microtia (present) , Short palm (present) , Generalized lipodystrophy (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
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Pathogenic
(Apr 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mandibular hypoplasia-deafness-progeroid syndrome
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003818445.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 26, 2019)
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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: SCV001216389.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect POLD1 protein function (PMID: 23770608, 30388038). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect POLD1 protein function (PMID: 23770608, 30388038). This variant has been observed in individual(s) with clinical features of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) (PMID: 23770608, 26350127, 28521875, 26172944). ClinVar contains an entry for this variant (Variation ID: 60775). This variant is not present in population databases (ExAC no frequency). This variant, c.1812_1814del, results in the deletion of 1 amino acid(s) of the POLD1 protein (p.Ser605del), but otherwise preserves the integrity of the reading frame. (less)
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Pathogenic
(Dec 15, 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: SCV004722168.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The POLD1 c.1812_1814delCTC variant is predicted to result in an in-frame deletion (p.Ser605del). This variant is the most frequently reported genetic cause of mandibular hypoplasia, … (more)
The POLD1 c.1812_1814delCTC variant is predicted to result in an in-frame deletion (p.Ser605del). This variant is the most frequently reported genetic cause of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and has been reported de novo in the vast majority of affected individuals (Weedon et al. 2013. PubMed ID: 23770608; Lessel et al. 2015. PubMed ID: 26172944; Sasaki et al. 2018. PubMed ID: 29199204; Wang et al. 2018. PubMed ID: 30023403; Yu et al. 2021. PubMed ID: 33369179). This variant is located within the polymerase active site of POLD1, and in vitro functional studies have demonstrated that this variant leads to a total loss of polymerase activity and moderately reduced 3' exonuclease activity (~40%) compared to wild type (Weedon et al. 2013. PubMed ID: 23770608; Oh et al. 2020. PubMed ID: 31944473). Additional in vitro studies also reported a delayed response to DNA damage and increased rates of telomere shortening compared to wild type (Fiorello et al. 2018. PubMed ID: 30388038; Murdocca et al. 2021. PubMed ID: 33618333). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is interpreted as pathogenic by multiple sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/60775/). Of note, this variant is located outside the 3' exonuclease domain associated with increased colorectal cancer risk and, to our knowledge, has not been reported in association with polyposis or colorectal cancer. Therefore, this variant is interpreted as pathogenic for MDPL syndrome but is considered a variant of uncertain significance for colorectal cancer susceptibility. (less)
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Pathogenic
(May 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000671207.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.1812_1814delCTC pathogenic mutation (also known as p.S605del) is located in coding exon 14 of the POLD1 gene. This pathogenic mutation results from an in-frame … (more)
The c.1812_1814delCTC pathogenic mutation (also known as p.S605del) is located in coding exon 14 of the POLD1 gene. This pathogenic mutation results from an in-frame CTC deletion at nucleotide positions 1812 to 1814. This results in the in-frame deletion of a serine at codon 605. This alteration has been reported as de novo in multiple individuals with mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome (Lessel D et al. Hum. Mutat., 2015 Nov;36:1070-9; Reinier F et al. Metab. Clin. Exp., 2015 Nov;64:1530-40; Weedon MN et al. Nat. Genet., 2013 Aug;45:947-50; Chen et al Int. J. Clin. Exp. Med.,2017;10(2):3876-3883). However, c.1812_1814delCTC has not, to our knowledge, been reported in individuals with polyposis or colorectal cancer. This alteration occurs in a highly conserved region of the catalytic subunit of the polymerase, and in vitro functional analysis demonstrated that the catalytic activity of the enzyme is reduced by this alteration (Weedon MN et al. Nat. Genet., 2013 Aug;45:947-50). Based on the available evidence, this alteration is interpreted as a disease causing mutation in association with MDPL syndrome; however, the clinical significance in regards to polyposis and colorectal cancer remains unclear. (less)
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Pathogenic
(May 01, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000708158.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Aug 01, 2013)
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no assertion criteria provided
Method: literature only
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MANDIBULAR HYPOPLASIA, DEAFNESS, PROGEROID FEATURES, AND LIPODYSTROPHY SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000083020.2
First in ClinVar: Aug 30, 2013 Last updated: Sep 14, 2015 |
Comment on evidence:
In 4 unrelated patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; 615381), Weedon et al. (2013) identified a de novo heterozygous in-frame … (more)
In 4 unrelated patients with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL; 615381), Weedon et al. (2013) identified a de novo heterozygous in-frame 3-bp deletion (c.1812_1814delCTC, NM_002691.2) in the POLD1 gene, resulting in the deletion of residue ser605 (ser605del) in motif A, a highly conserved region of the polymerase active site. The mutation, which was initially found by exome sequencing and confirmed by Sanger sequencing in 2 of the patients, was not found in any of the parents or in several large control databases. In vitro functional expression studies in E. coli showed that the mutant enzyme had lost its DNA polymerase ability, whereas its exonuclease activity, although decreased compared to wildtype, was still present. These studies demonstrated decoupling of the mutant enzyme's activities and suggested that the mutant protein could bind DNA, but was unable to interact with and incorporate dNTPs. The findings implicated POLD1 in adipose tissue homeostasis. (less)
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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
HelpTitle | Author | Journal | Year | Link |
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Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene. | Fiorillo C | DNA and cell biology | 2018 | PMID: 30388038 |
Mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome in the context of inherited lipodystrophies. | Reinier F | Metabolism: clinical and experimental | 2015 | PMID: 26350127 |
POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome. | Lessel D | Human mutation | 2015 | PMID: 26172944 |
An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. | Weedon MN | Nature genetics | 2013 | PMID: 23770608 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POLD1 | - | - | - | - |
Text-mined citations for rs398122386 ...
HelpRecord last updated May 27, 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.