NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter) AND Maturity-onset diabetes of the young type 3

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 2, 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:: RCV001249012.10

Allele description [Variation Report for NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)]

NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)

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.526C>T (p.Gln176Ter)

Other names:

NM_000545.8(HNF1A):c.526C>T

HGVS:

NC_000012.12:g.120989032C>T
NG_011731.2:g.15287C>T
NM_000545.8:c.526C>TMANE SELECT
NM_001306179.2:c.526C>T
NP_000536.6:p.Gln176Ter
NP_001293108.2:p.Gln176Ter
LRG_522t1:c.526C>T
GRCh37chr12:g.121426835C>T
LRG_522:g.15287C>T
NC_000012.11:g.121426835C>T
NC_000012.11:g.121426835C>T
NM_000545.5:c.526C>T
NM_000545.6(HNF1A):c.526C>T
NM_000545.6:c.526C>T
p.Gln176Ter

Protein change:

Q176*

Links:

dbSNP: rs754728827

NCBI 1000 Genomes Browser:

rs754728827

Molecular consequence:

NM_000545.8:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001306179.2:c.526C>T - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

protein loss of function [Variation Ontology: 0043]

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
SCV001422862	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 12107757, 25741868 Citation Link,
SCV002562136	Geisinger Clinic, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2022)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 36257325
SCV002762713	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Mar 23, 2022)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12107757, 32238361, 34440499 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422862

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 22, 2020)

germline

curation

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

Citation Link,

SCV002562136

Geisinger Clinic, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 2, 2022)

germline

research

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

SCV002762713

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Mar 23, 2022)

unknown

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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	curation
not provided	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

Mirshahi UL, Colclough K, Wright CF, Wood AR, Beaumont RN, Tyrrell J, Laver TW, Stahl R, Golden A, Goehringer JM; Geisinger-Regeneron DiscovEHR Collaboration., Frayling TF, Hattersley AT, Carey DJ, Weedon MN, Patel KA.

Am J Hum Genet. 2022 Nov 3;109(11):2018-2028. doi: 10.1016/j.ajhg.2022.09.014. Epub 2022 Oct 17.

PubMed [citation]

PMID:: 36257325
PMCID:: PMC9674944

See all PubMed Citations (5)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422862.2

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

Description

The p.Gln176Ter variant in HNF1A has been reported in 1 Southern Chinese family with maturity-onset diabetes of the young type 3 (MODY3) and has been identified in 0.0008856% (1/112922) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754728827). This variant has also been reported in ClinVar (VariationID: 372380) as pathogenic by GeneDx. In vitro functional studies in HeLa cells transfected with the variant demonstrating null expression and transactivation activities similar to those of an empty vector alone provide some evidence that the p.Gln176Ter variant may impact protein function (PMID: 12107757). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 576, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY3. In summary, this variant meets criteria to be classified as pathogenic for MODY3 in an autosomal dominant manner based on the prediction that it will cause loss of function of the HNF1A gene, low frequency of the variant in the general population, and in vitro functional studies. ACMG/AMP Criteria applied: PVS1, PM2, PS3_moderate (Richards 2015).

#	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 Geisinger Clinic, Geisinger Health System, SCV002562136.1

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

Description

PVS1, PM2, PS4, PP1_Supporting, PP4_Moderate

#	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		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV002762713.1

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

Description

The HNF1A c.526C>T (p.Gln176Ter) nonsense variant results in the substitution of glutamine at amino acid position 176 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in a heterozygous state in at least six individuals with maturity onset diabetes of the young (Xu et al. 2002; Ma et al. 2020; Gaál et al. 2021). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). In vitro studies in HeLa cells transfected with the c.526C>T variant demonstrated that the c.526C>T variant resulted in null expression and no detectable protein. Transactivation studies using a luciferase reporter assay showed 24.16% activity compared to wildtype, which was similar to an empty vector alone (Xu et al. 2002). Based on the available evidence, the c.526C>T (p.Gln176Ter) variant is classified as pathogenic for maturity onset diabetes of the young.

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

Last Updated: Sep 29, 2024

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