rs1800575

Variant names:

• chr17-37739455-G-A
• rs1800575
• NM_000458.4:c.529C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-37739455-G-A
• chr17-37739455-G-C
• chr17-37739455-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000458.4(HNF1B):​c.529C>T​(p.Arg177*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1B NM_000458.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.86

Genes affected

HNF1B (HGNC:11630): (HNF1 homeobox B) This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-37739455-G-A is Pathogenic according to our data. Variant chr17-37739455-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-37739455-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1B	NM_000458.4	c.529C>T	p.Arg177*	stop_gained	Exon 2 of 9	ENST00000617811.5	NP_000449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1B	ENST00000617811.5	c.529C>T	p.Arg177*	stop_gained	Exon 2 of 9	1	NM_000458.4	ENSP00000480291.1
HNF1B	ENST00000621123.4	c.529C>T	p.Arg177*	stop_gained	Exon 2 of 9	1		ENSP00000482711.1
HNF1B	ENST00000613727.4	c.529C>T	p.Arg177*	stop_gained	Exon 2 of 7	1		ENSP00000477524.1
HNF1B	ENST00000614313.4	c.529C>T	p.Arg177*	stop_gained	Exon 2 of 8	5		ENSP00000482529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal cysts and diabetes syndrome Pathogenic:3

Jul 06, 2019

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are all reported mechanisms of disease in this gene and are associated with type 2 diabetes mellitus (MIM#125853) and renal cysts and diabetes syndrome (MIM#137920; OMIM, PMID: 25536396, 11845238, 15509593). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant interfamilial and intrafamilial variability associated with HNF1B-related nephropathy (PMID: 33305128). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five individuals with kidney disease, including those with cystic kidneys (ClinVar, VCGS internal cohort, PMID: 31131422). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:3

Mar 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg177*) in the HNF1B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1B are known to be pathogenic (PMID: 9398836, 12148114, 15068978, 20378641). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of renal cysts and diabetes syndrome (PMID: 9398836, 12148114). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12635). For these reasons, this variant has been classified as Pathogenic. -

Nov 02, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect due to a loss of transactivation activity, as well as a dominant negative effect and altered protein localization specific to certain cell types (Tomura et al., 1999); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9398836, 12148114, 31131422, 32939031, 10224045) -

Type 2 diabetes mellitus;C0431693:Renal cysts and diabetes syndrome;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Feb 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	49
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.97
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800575; hg19: chr17-36099446;