VCV000407993.25 - ClinVar

NM_002691.4(POLD1):c.1930G>A (p.Asp644Asn)

Germline

Classification

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.

(7)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002691.4(POLD1):c.1930G>A (p.Asp644Asn)

Variation ID: 407993 Accession: VCV000407993.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.33 19: 50409159 (GRCh38) [ NCBI UCSC ] 19: 50912416 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Apr 29, 2017	Sep 29, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002691.4:c.1930G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002682.2:p.Asp644Asn	missense
NM_001256849.1:c.1930G>A	NP_001243778.1:p.Asp644Asn	missense
NM_001308632.1:c.2008G>A	NP_001295561.1:p.Asp670Asn	missense
NR_046402.2:n.1975G>A		non-coding transcript variant
NC_000019.10:g.50409159G>A
NC_000019.9:g.50912416G>A
NG_033800.1:g.29837G>A
LRG_785:g.29837G>A
LRG_785t1:c.1930G>A	LRG_785p1:p.Asp644Asn
LRG_785t2:c.2008G>A	LRG_785p2:p.Asp670Asn

... more HGVS ... less HGVS

Protein change

D644N, D670N

Other names

Canonical SPDI

NC_000019.10:50409158:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00006

Links

ClinGen: CA9596330 dbSNP: rs763465385 VarSome

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
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
POLD1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4946	4996

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 Help 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.
Colorectal cancer, susceptibility to, 10	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2023	RCV000476279.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 28, 2024	RCV000479873.8
Colorectal cancer, susceptibility to, 10 Mandibular hypoplasia-deafness-progeroid syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764225.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2024	RCV002268073.7
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 15, 2021	RCV002256264.3
POLD1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Oct 17, 2022	RCV004529593.1

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.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal cancer, susceptibility to, 10 Mandibular hypoplasia-deafness-progeroid syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895228.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Apr 15, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534611.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: To the best of our knowledge, the c.1930G>A (p.D644N) variant has not been reported in individuals with POLD1-related disease. It was observed in 4/35400 chromosomes … (more) To the best of our knowledge, the c.1930G>A (p.D644N) variant has not been reported in individuals with POLD1-related disease. It was observed in 4/35400 chromosomes of the Latino subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 407993). In silico tools suggest the impact of the variant on protein function is benign, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
Uncertain significance (Sep 08, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Colorectal cancer, susceptibility to, 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000547540.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: 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 … (more) 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 407993). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs763465385, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 644 of the POLD1 protein (p.Asp644Asn). (less)
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002551940.6 First in ClinVar: Jul 28, 2022 Last updated: Aug 04, 2024
Uncertain significance (Feb 28, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000571799.7 First in ClinVar: Apr 29, 2017 Last updated: Sep 29, 2024	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; … (more) 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; This variant is associated with the following publications: (PMID: 32041611, 20951805) (less)
Uncertain significance (Oct 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	POLD1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004105292.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The POLD1 c.1930G>A variant is predicted to result in the amino acid substitution p.Asp644Asn. This variant was reported in a dyslipidemia cohort study (Supplemental Tables … (more) The POLD1 c.1930G>A variant is predicted to result in the amino acid substitution p.Asp644Asn. This variant was reported in a dyslipidemia cohort study (Supplemental Tables 3 and 4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50912416-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005194774.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024

Comment:

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 407993). This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is present in population databases (rs763465385, gnomAD 0.01%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 644 of the POLD1 protein (p.Asp644Asn).

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; This variant is associated with the following publications: (PMID: 32041611, 20951805)

Comment:

The POLD1 c.1930G>A variant is predicted to result in the amino acid substitution p.Asp644Asn. This variant was reported in a dyslipidemia cohort study (Supplemental Tables 3 and 4, Dron et al. 2020. PubMed ID: 32041611). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-50912416-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.

Comment:

Citations for germline classification of this variant

There 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 rs763465385 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_002691.4(POLD1):c.1930G>A (p.Asp644Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs763465385 ...