VCV000214289.15 - ClinVar

NM_080916.3(DGUOK):c.758A>G (p.Asn253Ser)

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.

(6)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_080916.3(DGUOK):c.758A>G (p.Asn253Ser)

Variation ID: 214289 Accession: VCV000214289.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.1 2: 73958196 (GRCh38) [ NCBI UCSC ] 2: 74185323 (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	Dec 6, 2016	Oct 8, 2024	Apr 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_080916.3:c.758A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_550438.1:p.Asn253Ser	missense
NM_001318859.2:c.476A>G	NP_001305788.1:p.Asn159Ser	missense
NM_001318860.2:c.467A>G	NP_001305789.1:p.Asn156Ser	missense
NM_001318861.2:c.467A>G	NP_001305790.1:p.Asn156Ser	missense
NM_001318862.2:c.449A>G	NP_001305791.1:p.Asn150Ser	missense
NM_001318863.2:c.449A>G	NP_001305792.1:p.Asn150Ser	missense
NM_080918.3:c.494A>G	NP_550440.1:p.Asn165Ser	missense
NR_104029.1:n.343T>C		non-coding transcript variant
NR_104030.1:n.317T>C		non-coding transcript variant
NR_134893.2:n.412A>G		non-coding transcript variant
NR_134894.2:n.560A>G		non-coding transcript variant
NR_134895.2:n.224A>G		non-coding transcript variant
NR_134896.2:n.394A>G		non-coding transcript variant
NR_134897.2:n.604A>G		non-coding transcript variant
NR_134898.2:n.528A>G		non-coding transcript variant
NC_000002.12:g.73958196A>G
NC_000002.11:g.74185323A>G
NG_008044.1:g.36371A>G

... more HGVS ... less HGVS

Protein change

N253S, N165S, N159S, N150S, N156S

Other names

p.N253S:AAT>AGT
p.Asn253Ser

Canonical SPDI

NC_000002.12:73958195:A:G

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.

0.00020 (G)

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

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA322951 dbSNP: rs200169027 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.
DGUOK		-	-	GRCh38 GRCh37	234	371
DGUOK-AS1	-	-	-	GRCh38	-	50

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.
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 12, 2023	RCV000726205.13
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2023	RCV003298259.2
DGUOK-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 2, 2024	RCV004751359.1

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.
Likely benign (Oct 18, 2011)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000251328.10 First in ClinVar: Oct 11, 2015 Last updated: Apr 17, 2019	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Uncertain significance (Jun 08, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000342881.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DGUOK Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Sep 10, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002180182.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Comment: This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 253 of the DGUOK protein (p.Asn253Ser). … (more) This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 253 of the DGUOK protein (p.Asn253Ser). This variant is present in population databases (rs200169027, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DGUOK-related conditions. ClinVar contains an entry for this variant (Variation ID: 214289). 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 DGUOK protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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)
Uncertain significance (Jan 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002541844.2 First in ClinVar: Jul 09, 2022 Last updated: Jan 26, 2024	Comment: BP4, PM2 Number of individuals with the variant: 2
Uncertain significance (Apr 28, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003995329.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.758A>G (p.N253S) alteration is located in exon 6 (coding exon 6) of the DGUOK gene. This alteration results from a A to G substitution … (more) The c.758A>G (p.N253S) alteration is located in exon 6 (coding exon 6) of the DGUOK gene. This alteration results from a A to G substitution at nucleotide position 758, causing the asparagine (N) at amino acid position 253 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jul 02, 2024)	no assertion criteria provided Method: clinical testing	DGUOK-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005351309.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DGUOK c.758A>G variant is predicted to result in the amino acid substitution p.Asn253Ser. To our knowledge, this variant has not been reported in the … (more) The DGUOK c.758A>G variant is predicted to result in the amino acid substitution p.Asn253Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 253 of the DGUOK protein (p.Asn253Ser). This variant is present in population databases (rs200169027, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DGUOK-related conditions. ClinVar contains an entry for this variant (Variation ID: 214289). 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 DGUOK protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

Comment:

The c.758A>G (p.N253S) alteration is located in exon 6 (coding exon 6) of the DGUOK gene. This alteration results from a A to G substitution at nucleotide position 758, causing the asparagine (N) at amino acid position 253 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

The DGUOK c.758A>G variant is predicted to result in the amino acid substitution p.Asn253Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. 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

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DGUOK	-	-	-	-

Text-mined citations for rs200169027 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_080916.3(DGUOK):c.758A>G (p.Asn253Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs200169027 ...