NM_000458.4(HNF1B):c.344G>A (p.Ser115Asn) AND Renal cysts and diabetes syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 2, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000030527.7

Allele description [Variation Report for NM_000458.4(HNF1B):c.344G>A (p.Ser115Asn)]

NM_000458.4(HNF1B):c.344G>A (p.Ser115Asn)

Gene:

HNF1B:HNF1 homeobox B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q12

Genomic location:

Preferred name:

NM_000458.4(HNF1B):c.344G>A (p.Ser115Asn)

HGVS:

NC_000017.11:g.37744541C>T
NG_013019.2:g.5566G>A
NM_000458.4:c.344G>AMANE SELECT
NM_001165923.4:c.344G>A
NM_001304286.2:c.344G>A
NP_000449.1:p.Ser115Asn
NP_001159395.1:p.Ser115Asn
NP_001291215.1:p.Ser115Asn
NC_000017.10:g.36104532C>T
NM_000458.2:c.344G>A
NM_000458.3:c.344G>A

Protein change:

S115N

Links:

Molecular consequence:

NM_000458.4:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001165923.4:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001304286.2:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Renal cysts and diabetes syndrome (RCAD)
Synonyms:: MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 5; MODY type 5; Hyperuricemic nephropathy, familial juvenile, atypical; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007669; MedGen: C0431693; Orphanet: 93111; OMIM: 137920

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053198	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation, clinical testing	Citation Link,
SCV000926159	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 6, 2019)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002768333	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11845238, 15509593, 25536396, 29764441, 2976441, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000053198

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

likely pathogenic
(Aug 18, 2011)

germline

curation, clinical testing

Citation Link,

SCV000926159

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 6, 2019)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002768333

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, literature only, curation
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of a gain-of-function mutation in the HNF-1beta gene in a Japanese family with MODY.

Yoshiuchi I, Yamagata K, Zhu Q, Tamada I, Takahashi Y, Onigata K, Takeda J, Miyagawa J, Matsuzawa Y.

Diabetologia. 2002 Jan;45(1):154-5. No abstract available.

PubMed [citation]

PMID:: 11845238

HNF1beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment.

Barbacci E, Chalkiadaki A, Masdeu C, Haumaitre C, Lokmane L, Loirat C, Cloarec S, Talianidis I, Bellanne-Chantelot C, Cereghini S.

Hum Mol Genet. 2004 Dec 15;13(24):3139-49. Epub 2004 Oct 27.

PubMed [citation]

PMID:: 15509593

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000053198.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided
2	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	not provided
2	germline	unknown	not provided	Blood	assert pathogenicity		not provided	not provided	not provided	See 2

Co-occurrences

#	Zygosity	Alleles	Number of Observations
2	SingleHeterozygote	HNF4A:c.201C>T, HNF4A:c.116-5C>T, TCF1:c.79A>C, TCF1:c.51C>G, TCF1:c.1501+7G>A, TCF1:c.1460G>A, TCF1:c.1375C>T, TCF1:c.1720A>G	1

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV000926159.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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. Variable types and ages of onset of renal disease have been associated with HNF1B variants (PMID: 2976441). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. This variant is in the last coding base of exon 1 and is therefore in a splice region. (SB) 0600 - Variant is located in the annotated hepatocyte nuclear factor 1 N-terminus domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual observed by a clinical laboratory in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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