NM_000545.8(HNF1A):c.335C>T (p.Pro112Leu) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 13, 2023
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:: RCV000517471.7

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000613611	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 7, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 21518407, 15657605, 18003757, 24915262, 26431509, 11162430, 12107757, 12574234, 17989309, 26467025
SCV002513014	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 4, 2022)	germline	clinical testing	Citation Link,
SCV004295423	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21518407, 11162430, 27899486, 35472491, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000613611

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Dec 7, 2016)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002513014

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 4, 2022)

germline

clinical testing

Citation Link,

SCV004295423

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 13, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients.

Xu JY, Dan QH, Chan V, Wat NM, Tam S, Tiu SC, Lee KF, Siu SC, Tsang MW, Fung LM, Chan KW, Lam KS.

Eur J Hum Genet. 2005 Apr;13(4):422-7.

PubMed [citation]

PMID:: 15657605

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 (13)

Details of each submission

From Athena Diagnostics, SCV000613611.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	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

From GeneDx, SCV002513014.2

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

Description

Published functional studies demonstrate impaired DNA binding and significantly reduced transcriptional activity (Bjrkhaug et al., 2000; Xu et al., 2002; Najmi et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17989309, 12107757, 12574234, 15657605, 27899486, 26431509, 24915262, 18003757, 12453420, 11162430, 21518407, 32910913)

#	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 Invitae, SCV004295423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the HNF1A protein (p.Pro112Leu). This variant is present in population databases (rs137853243, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (MODY) (PMID: 11162430, 21518407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HNF1A function (PMID: 11162430, 27899486, 35472491). For these reasons, this variant has been classified as Pathogenic.

#	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: May 7, 2024

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