NM_000545.8(HNF1A):c.2T>C (p.Met1Thr) AND Maturity onset diabetes mellitus in young

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Dec 7, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002440900.2

Allele description

NM_000545.8(HNF1A):c.2T>C (p.Met1Thr)

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.2T>C (p.Met1Thr)

Other names:

NM_001306179.2:c.2T>C

HGVS:

NC_000012.12:g.120978770T>C
NG_011731.2:g.5025T>C
NM_000545.8:c.2T>CMANE SELECT
NM_001306179.2:c.2T>C
NP_000536.6:p.Met1Thr
NP_001293108.2:p.Met1Thr
LRG_522t1:c.2T>C
LRG_522:g.5025T>C
NC_000012.11:g.121416573T>C
NM_000545.5:c.2T>C

Protein change:

M1T

Links:

dbSNP: rs2135819325

NCBI 1000 Genomes Browser:

rs2135819325

Molecular consequence:

NM_000545.8:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001306179.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000545.8:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Maturity onset diabetes mellitus in young (MODY)
Synonyms:: Mason type diabetes
Identifiers:: MONDO: MONDO:0018911; MedGen: C0342276; Orphanet: 552; OMIM: 606391; Human Phenotype Ontology: HP:0004904

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002748828	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Likely pathogenic (Apr 8, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18003757, 23348805 Citation Link,
SCV004848879	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 7, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23348805, 18003757, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002748828

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Likely pathogenic
(Apr 8, 2016)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004848879

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Dec 7, 2022)

germline

clinical testing

PubMed (3)
[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	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia.

Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S.

Hum Mutat. 2013 May;34(5):669-85. doi: 10.1002/humu.22279. Epub 2013 Apr 2.

PubMed [citation]

PMID:: 23348805

The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.

Bellanné-Chantelot C, Carette C, Riveline JP, Valéro R, Gautier JF, Larger E, Reznik Y, Ducluzeau PH, Sola A, Hartemann-Heurtier A, Lecomte P, Chaillous L, Laloi-Michelin M, Wilhem JM, Cuny P, Duron F, Guerci B, Jeandidier N, Mosnier-Pudar H, Assayag M, Dubois-Laforgue D, Velho G, et al.

Diabetes. 2008 Feb;57(2):503-8. Epub 2007 Nov 14.

PubMed [citation]

PMID:: 18003757

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV002748828.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the HNF1A gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. This variant has been detected in three families with clinical diagnoses of MODY; however, specific phenotype information was not provided (Bellanné-Chantelot C, Diabetes 2008 Feb; 57(2):503-8; Colclough K, Hum. Mutat. 2013 May; 34(5):669-85.). Of note, the nucleotide changes observed in these studies, which all result in the same p.M1? alteration, include c.1A>C, c.1A>T, and c.2T>C. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6449 samples (12898 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation or N-terminal truncation, this alteration is interpreted as likely pathogenic (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848879.1

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

Description

The p.Met1? (c.2T>C) variant in HNF1A has been reported in 1 individual with maturity-onset diabetes of the young (MODY) (Colclough 2013 PMID: 23348805). It was absent from large population studies. This variant was classified as Likely Pathogenic on Mar 4, 2022 by the ClinGen-approved Monogenic Diabetes expert panel (Variation ID 1342949). It affects the translation initiation start codon (ATG) and is therefore predicted to disrupt translation although a variety of outcomes (no protein synthesis or the activation of an downstream translation initiation codon) are possible. Additional variants involving the initiation codon (c.1A>C, c.1A>T) have been identified in individuals with MODY (Colclough 2013 PMID: 23348805, Bellanné-Chantelot 2008 PMID: 18003757), supporting that this change may not be tolerated. Loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant MODY. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PM2_P.

#	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: Apr 20, 2024

ClinVar

Relating variation to medicine