VCV000635633.40 - ClinVar

NM_000458.4(HNF1B):c.865A>G (p.Asn289Asp)

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.

(3)

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/Likely 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_000458.4(HNF1B):c.865A>G (p.Asn289Asp)

Variation ID: 635633 Accession: VCV000635633.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q12 17: 37731775 (GRCh38) [ NCBI UCSC ] 17: 36091766 (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	Jul 15, 2019	Nov 11, 2023	Jul 9, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000458.4:c.865A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000449.1:p.Asn289Asp	missense
NM_001165923.4:c.787A>G	NP_001159395.1:p.Asn263Asp	missense
NM_001304286.2:c.787A>G	NP_001291215.1:p.Asn263Asp	missense
NC_000017.11:g.37731775T>C
NC_000017.10:g.36091766T>C
NG_013019.2:g.18332A>G

... more HGVS ... less HGVS

Protein change

N289D, N263D

Other names

Canonical SPDI

NC_000017.11:37731774:T:C

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.

Links

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.
HNF1B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	638	855

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.
Renal cysts and diabetes syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 6, 2019	RCV000787125.5
Nonpapillary renal cell carcinoma Renal cysts and diabetes syndrome Type 2 diabetes mellitus	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2021	RCV002493434.3
Hyperechogenic kidneys	Likely pathogenic (1)	criteria provided, single submitter	Jul 9, 2022	RCV003106062.6

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 (Jul 06, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: literature only	Renal cysts and diabetes syndrome Affected status: yes Allele origin: germline	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV000926054.1 First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019 Comment: This variant and it's classification has been reported by Vasileiou et al. 2019; DOI:10.1101/576918. The variants has previously been reported in PMID:25700310; PMID:21775974; PMID:25536396 as … (more) This variant and it's classification has been reported by Vasileiou et al. 2019; DOI:10.1101/576918. The variants has previously been reported in PMID:25700310; PMID:21775974; PMID:25536396 as "c.865A>G; c.865A>G" with clinical significance Pathogenic. It has been re-classified using InterVar and manual curation as Pathogenic based on PS2 PM1 PM2 PP3 PP5. (less)	Publications: PubMed (3) PubMed: 25700310‚ 21775974‚ 25536396 DOI: 10.1101/576918 DOI: 10.1101/576918
Likely pathogenic (Jul 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hyperechogenic kidneys Affected status: yes Allele origin: maternal	Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center Accession: SCV002556335.2 First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023	Publications: PubMed (3) PubMed: 31498910‚ 21775974‚ 33851123 Comment: The missense variant “NM_000458.4:c.865A>G” was classified as likely pathogenic using PM1+PM2_Supporting+PP1+PP3 +PP4+PM5 evidence. PM1: the Asn289Asp variant located in a DNA-Binding domain called POUH/Homeo, and … (more) The missense variant “NM_000458.4:c.865A>G” was classified as likely pathogenic using PM1+PM2_Supporting+PP1+PP3 +PP4+PM5 evidence. PM1: the Asn289Asp variant located in a DNA-Binding domain called POUH/Homeo, and the homeodomain and the second half of the N-terminal domain (“HNF-1_N”) host the two mutational hot spots for missense variants.[PMID: 31498910] PM2_Supporting: the population frequency of this variant is absent in gnomAD, ExAc and 1000Genome database; PP1: this variant was inherited from the mother, and PMID: 21775974 also reported this splice variant as pathogenic; PP3:14 out of 17 softwares predicted damaging and 4 softwares predicted conserved in VarCards, and the REVEL score is 0.790; PP4: the isolated bilateral hyperechogenic kidneys phenotype of the fetal is highly specific for the genetic etiology of HNF1B disases; PM5: in article PMID:33851123, an alternative variant chr17:36091766 T>G (Asn289His) is classified likely pathogenic according to ACMG guidelines. (less)
Likely pathogenic (Sep 13, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Type 2 diabetes mellitus Renal cysts and diabetes syndrome Nonpapillary renal cell carcinoma Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002793993.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022

Comment:

The missense variant “NM_000458.4:c.865A>G” was classified as likely pathogenic using PM1+PM2_Supporting+PP1+PP3 +PP4+PM5 evidence. PM1: the Asn289Asp variant located in a DNA-Binding domain called POUH/Homeo, and the homeodomain and the second half of the N-terminal domain (“HNF-1_N”) host the two mutational hot spots for missense variants.[PMID: 31498910] PM2_Supporting: the population frequency of this variant is absent in gnomAD, ExAc and 1000Genome database; PP1: this variant was inherited from the mother, and PMID: 21775974 also reported this splice variant as pathogenic; PP3:14 out of 17 softwares predicted damaging and 4 softwares predicted conserved in VarCards, and the REVEL score is 0.790; PP4: the isolated bilateral hyperechogenic kidneys phenotype of the fetal is highly specific for the genetic etiology of HNF1B disases; PM5: in article PMID:33851123, an alternative variant chr17:36091766 T>G (Asn289His) is classified likely pathogenic according to ACMG guidelines.

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
Autosomal Dominant Tubulointerstitial Kidney Disease HNF1B With Maturity-Onset Diabetes of the Young: A Case Report With Kidney Biopsy.	Oba Y	Kidney medicine	2020	PMID: 33851123
Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome?	Vasileiou G	Prenatal diagnosis	2019	PMID: 31498910
A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update.	Alvelos MI	Medicine	2015	PMID: 25700310
HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum.	Clissold RL	Nature reviews. Nephrology	2015	PMID: 25536396
Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood.	Faguer S	Kidney international	2011	PMID: 21775974
-	-	-	-	DOI: 10.1101/576918

Text-mined citations for this variant ...

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000458.4(HNF1B):c.865A>G (p.Asn289Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...