VCV000135641.16 - ClinVar

NM_003647.3(DGKE):c.966G>A (p.Trp322Ter)

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.

(8)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003647.3(DGKE):c.966G>A (p.Trp322Ter)

Variation ID: 135641 Accession: VCV000135641.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q22 17: 56848773 (GRCh38) [ NCBI UCSC ] 17: 54926134 (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	Jun 13, 2014	Nov 24, 2024	Aug 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_003647.3:c.966G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003638.1:p.Trp322Ter	nonsense
NC_000017.11:g.56848773G>A
NC_000017.10:g.54926134G>A
NG_033888.1:g.19675G>A

Protein change

W322*

Other names

Canonical SPDI

NC_000017.11:56848772: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.

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

The Genome Aggregation Database (gnomAD) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00016

Links

ClinGen: CA332175 OMIM: 601440.0004 dbSNP: rs138924661 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.
DGKE		-	-	GRCh38 GRCh37	218	231

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.
AHUS, SUSCEPTIBILITY TO, 7	risk factor (1)	no assertion criteria provided	May 1, 2013	RCV000043567.3
Atypical hemolytic-uremic syndrome	Pathogenic (2)	criteria provided, single submitter	Apr 1, 2020	RCV000122617.3
Immunoglobulin-mediated membranoproliferative glomerulonephritis	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 7, 2022	RCV000760165.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Aug 29, 2024	RCV001854681.5

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.
Pathogenic (Mar 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Immunoglobulin-mediated membranoproliferative glomerulonephritis (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Center for Precision Medicine, Vanderbilt University Medical Center Accession: SCV000889982.1 First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019	Publications: PubMed (1) PubMed: 29590070 Number of individuals with the variant: 15 Clinical Features: chronic renal failure (present) , acute renal failure (present) , nephritis/nephrosis/renal sclerosis (present) , proteinuria (present) , hemolytic-uremic syndrome (present) , acquired hemolytic anemias (present) … (more) chronic renal failure (present) , acute renal failure (present) , nephritis/nephrosis/renal sclerosis (present) , proteinuria (present) , hemolytic-uremic syndrome (present) , acquired hemolytic anemias (present) , thrombocytopenia (present) (less) Method: A phenotype risk score (PheRS) for Nephrotic Syndrome, Type 7 disease was calculated by mapping the disease HPO terms to phecodes, clustered ICD-9 codes that represent phenotypes in the electronic health records. When applied to 21,701 European individuals, the PheRS for this disease showed significant association with the rs138924661 variant. Some individuals that are heterozygous or homozygous for this variant have phecodes that are consistent with phenotypes associated with this disease. 2 of the 15 individuals carrying this allele underwent kidney transplants.
Pathogenic (Jun 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunoglobulin-mediated membranoproliferative glomerulonephritis Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368100.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Atypical hemolytic-uremic syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002587670.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Pathogenic (Dec 07, 2023)	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: SCV002234882.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 23274426‚ 23542698‚ 25135762‚ 25854283‚ 28496993 Comment: This sequence change creates a premature translational stop signal (p.Trp322) in the DGKE gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Trp322) in the DGKE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DGKE are known to be pathogenic (PMID: 23274426, 23542698). This variant is present in population databases (rs138924661, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with nephrotic syndrome and atypical hemolytic uremic syndrome (PMID: 23542698, 25135762, 25854283, 28496993). ClinVar contains an entry for this variant (Variation ID: 135641). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Immunoglobulin-mediated membranoproliferative glomerulonephritis Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810357.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413265.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (7) PubMed: 23542698‚ 25135762‚ 25854283‚ 28117080‚ 28496993‚ 29590070‚ 29869118 Comment: PP1, PM3_very_strong, PS4_moderate, PVS1 Number of individuals with the variant: 2
probable-pathogenic (-)	no assertion criteria provided Method: not provided	Atypical hemolytic uremic syndrome Affected status: not provided Allele origin: germline	Richard Lifton Laboratory, Yale University School of Medicine Accession: SCV000155124.1 First in ClinVar: Jun 13, 2014 Last updated: Jun 13, 2014 Comment: Autosomal recessive variant	Publications: PubMed (1) PubMed: 24747643 Comment: Converted during submission to Likely pathogenic.
risk factor (May 01, 2013)	no assertion criteria provided Method: literature only	HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 7 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000071437.2 First in ClinVar: Jun 05, 2013 Last updated: Jul 26, 2015	Publications: PubMed (1) PubMed: 23542698 Comment on evidence: In 2 sibs of European ancestry with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified a homozygous c.966G-A transition in the DGKE … (more) In 2 sibs of European ancestry with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified a homozygous c.966G-A transition in the DGKE gene, resulting in a trp322-to-ter (W322X) substitution in the kinase catalytic domain. The mutations were found by exome sequencing. Two additional patients with the disorder were also found to be homozygous for the W322X mutation, and haplotype analysis of the 3 families indicated a founder effect. Two further patients with a similar disorder carried the W322X mutation in compound heterozygosity with another mutation in the DGKE gene (see, e.g., S11X, 601440.0007). The W322X mutation was found in heterozygous state in 1 of 8,475 controls of European ancestry. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Trp322*) in the DGKE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DGKE are known to be pathogenic (PMID: 23274426, 23542698). This variant is present in population databases (rs138924661, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with nephrotic syndrome and atypical hemolytic uremic syndrome (PMID: 23542698, 25135762, 25854283, 28496993). ClinVar contains an entry for this variant (Variation ID: 135641). For these reasons, this variant has been classified as Pathogenic.

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
Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93.	Bezdíčka M	Pediatric nephrology (Berlin, Germany)	2018	PMID: 29869118
Phenotype risk scores identify patients with unrecognized Mendelian disease patterns.	Bastarache L	Science (New York, N.Y.)	2018	PMID: 29590070
Successful Application of Whole Genome Sequencing in a Medical Genetics Clinic.	Bick D	Journal of pediatric genetics	2017	PMID: 28496993
Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.	Bierzynska A	Kidney international	2017	PMID: 28117080
Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome.	Mele C	Clinical journal of the American Society of Nephrology : CJASN	2015	PMID: 25854283
Complement mutations in diacylglycerol kinase-ε-associated atypical hemolytic uremic syndrome.	Sánchez Chinchilla D	Clinical journal of the American Society of Nephrology : CJASN	2014	PMID: 25135762
Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors.	Goh G	Nature genetics	2014	PMID: 24747643
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome.	Lemaire M	Nature genetics	2013	PMID: 23542698
DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.	Ozaltin F	Journal of the American Society of Nephrology : JASN	2013	PMID: 23274426

Text-mined citations for rs138924661 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_003647.3(DGKE):c.966G>A (p.Trp322Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138924661 ...