NM_000545.8(HNF1A):c.1135C>G (p.Pro379Ala) AND Maturity-onset diabetes of the young type 3

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 30, 2023
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:: RCV001109486.13

Allele description [Variation Report for NM_000545.8(HNF1A):c.1135C>G (p.Pro379Ala)]

NM_000545.8(HNF1A):c.1135C>G (p.Pro379Ala)

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.1135C>G (p.Pro379Ala)

Other names:

NM_000545.8(HNF1A):c.1135C>G

HGVS:

NC_000012.12:g.120996568C>G
NG_011731.2:g.22823C>G
NM_000545.8:c.1135C>GMANE SELECT
NM_001306179.2:c.1135C>G
NP_000536.6:p.Pro379Ala
NP_001293108.2:p.Pro379Ala
LRG_522t1:c.1135C>G
LRG_522:g.22823C>G
NC_000012.11:g.121434371C>G
NC_000012.11:g.121434371C>G
NM_000545.5:c.1135C>G
NM_000545.6(HNF1A):c.1135C>G
NM_000545.6:c.1135C>G
p.Pro379Ala

Protein change:

P379A

Links:

dbSNP: rs754729248

NCBI 1000 Genomes Browser:

rs754729248

Molecular consequence:

NM_000545.8:c.1135C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.1135C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

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
SCV001266828	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21170474, 23139355, 23607861, 16917892, 18003757 Citation Link,
SCV001423042	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 22, 2020)	germline	curation	PubMed (9) [See all records that cite these PMIDs] 30202817, 23348805, 19754856, 21761282, 23607861, 30155490, 29207974, 16917892, 25741868 Citation Link,
SCV002318844	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15883474, 18003757, 15657605, 25741868
SCV002503611	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16917892, 18003757, 23139355, 23348805, 23607861, 29207974, 30202817, 31485449, 25741868

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	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Differential effects of HNF-1α mutations associated with familial young-onset diabetes on target gene regulation.

Galán M, García-Herrero CM, Azriel S, Gargallo M, Durán M, Gorgojo JJ, Andía VM, Navas MA.

Mol Med. 2011 Mar-Apr;17(3-4):256-65. doi: 10.2119/molmed.2010.00097. Epub 2010 Dec 15.

PubMed [citation]

PMID:: 21170474
PMCID:: PMC3060974

An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA.

Cervin C, Axler O, Holmkvist J, Almgren P, Rantala E, Tuomi T, Groop L, Dahlbäck B, Karlsson E.

J Intern Med. 2010 Mar;267(3):316-21. doi: 10.1111/j.1365-2796.2009.02145.x. Epub 2009 Jun 22.

PubMed [citation]

PMID:: 19754856

See all PubMed Citations (15)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001266828.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001423042.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (9)

Description

The p.Pro379Ala variant in HNF1A has been reported in 8 individuals with maturity-onset diabetes of the young type 3 (PMID: 19754856, 29207974, 23607861, 30202817, 30155490, 2176128) and has been Identified in 0.07914% (28/35382) of Latino chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). This variant has also been reported in ClinVar (VariationID: 431970) as likely pathogenic by GeneDx and as pathogenic by Fulgent Genetics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Ala have been reported in association with disease in the literature, suggesting that this variant is in a mutational hot spot and supports pathogenicity (PMID: 23348805, 16917892). Three additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Thr, p.Pro379Arg, and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 15883474, 30293189, 21683639, 26479152, 28012402). In summary the clinical significance of the p.Pro379Ala variant is uncertain. ACMG/AMP Criteria applied: BA1, PS4_moderate, PM1, PM5, PP3, (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 3billion, SCV002318844.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

Different missense changes at the same codon have been reported to be associated with HNF1A related disorder (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.964>=0.6). A missense variant is a common mechanism . It is observed in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset at total allele frequency of 0.000188. Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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

From Molecular Genetics, Royal Melbourne Hospital, SCV002503611.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change is predicted to replace proline with alanine at codon 379 of the HNF1A protein, p.(Pro379Ala). The proline residue is highly conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between proline and alanine. The variant is present in a large population cohort that incorporates multiple type 2 diabetes studies at a global frequency of 0.02% (rs754729248, 52/281432 alleles, 1 homozygote in gnomAD v2.1.1), and at 0.06% in the Latino population. It is present at a similar frequency of 0.02% (18/119738 alleles, 0 homozygotes) in the global gnomAD control cohort, but a reduced frequency of 0.03% in the controls of Latino background. This variant has been found in multiple cases diagnosed with different forms of diabetes including MODY3 (PMID: 18003757, 23348805, 23139355, 29207974, 30202817, 31485449), and is classified as likely pathogenic/pathogenic (ClinVar ID: 431970). Although the variant is more common in the population than expected for dominant disease, the prevalence of the variant in a MODY3 cohort (8/356, PMID: 18003757) is significantly increased compared with the prevalence in gnomAD controls. Additionally, this variant is present within small cohorts of HNF1A-MODY cases with significantly increased haemoglobin A1c and fasting glucose levels, and bile acid synthesis compared to healthy controls (PMID: 23139355, 23607861). The variant is located in the transactivation domain (PMID: 18003757), and functional studies have shown that Pro379Ala significantly increases activation of the CYP7A1 promoter compared to wild-type (PMID: 23607861). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms). Furthermore, four alternative missense changes at this position have been seen before in MODY3 cases (p.Pro379Thr, p.Pro379Ser, p.Pro379Arg, p.Pro379His; PMID: 18003757, 16917892). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4, PS3_Supporting, PP3.

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine