NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu) AND Maturity-onset diabetes of the young type 3

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 6, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000016080.28

Allele description [Variation Report for NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu)]

NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu)

Gene:

HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu)

Other names:

NM_000545.8(HNF1A):c.335C>T; p.Pro112Leu

HGVS:

NC_000012.12:g.120988841C>T
NG_011731.2:g.15096C>T
NM_000545.8:c.335C>TMANE SELECT
NM_001306179.2:c.335C>T
NP_000536.6:p.Pro112Leu
NP_001293108.2:p.Pro112Leu
LRG_522t1:c.335C>T
LRG_522:g.15096C>T
NC_000012.11:g.121426644C>T
NC_000012.11:g.121426644C>T
NM_000545.5:c.335C>T
p.PRO112LEU

Protein change:

P112L; PRO112LEU

Links:

OMIM: 142410.0015; dbSNP: rs137853243

NCBI 1000 Genomes Browser:

rs137853243

Molecular consequence:

NM_000545.8:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Maturity-onset diabetes of the young type 3
Synonyms:: Diabetes mellitus MODY type 3; MODY hepatocyte nuclear factor-1-alpha related; MODY type 3; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010894; MedGen: C1838100; Orphanet: 552; OMIM: 600496

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000036348	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2003)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11162430, 12107757, 12574234
SCV002767355	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11162430, 12107757, 21518407, 32238361, 32910913, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000036348

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2003)

germline

literature only

PubMed (3)
[See all records that cite these PMIDs]

SCV002767355

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2021)

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway.

Bjørkhaug L, Sagen JV, Thorsby P, Søvik O, Molven A, Njølstad PR.

J Clin Endocrinol Metab. 2003 Feb;88(2):920-31.

PubMed [citation]

PMID:: 12574234

MODY associated with two novel hepatocyte nuclear factor-1alpha loss-of-function mutations (P112L and Q466X).

Bjørkhaug L, Ye H, Horikawa Y, Søvik O, Molven A, Njølstad PR.

Biochem Biophys Res Commun. 2000 Dec 29;279(3):792-8.

PubMed [citation]

PMID:: 11162430

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000036348.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a 3-generation Norwegian family with MODY3 (600496), Bjorkhaug et al. (2000) found a C-to-T transition at nucleotide 358 in exon 2 of the HNF1A gene, leading to a pro112-to-leu (P112L) amino acid substitution, in all 3 affected members. The phenotype in this family was mild with mild fasting and postprandial hyperglycemia easily controlled by diet only. Diabetes-associated late complications were not observed. P112L mutant protein demonstrated a significantly reduced ability to bind a high affinity HNF1 binding site and to activate transcription. Immunolocalization studies in HeLa cells showed that P112L mutant protein was correctly targeted to the nucleus. Bjorkhaug et al. (2000) concluded that the P112L mutation seems to impair pancreatic beta-cell function by loss-of-function mechanisms.

Xu et al. (2002) found the HNF1A P112L mutation in a southern Chinese MODY family.

Bjorkhaug et al. (2003) found evidence for possible founder effect of the P112L mutation in the Norwegian population.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767355.1

#	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 Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type III maturity-onset diabetes of the young (MODY type III; MIM#600496). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA-binding domain (PMID: 32910913). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with MODY (ClinVar, PMIDs: 11162430, 12107757, 21518407, 32238361). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies performed by multiple laboratories have shown that it reduced protein expression, transcriptional activity, DNA binding and also resulted in impaired subcellular localisation (PMID: 32910913). (SP) 1205 - This variant has been shown to be maternally inherited. (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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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