NM_000545.8(HNF1A):c.1424C>T (p.Pro475Leu) AND Monogenic diabetes

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 1, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001248915.4

Allele description [Variation Report for NM_000545.8(HNF1A):c.1424C>T (p.Pro475Leu)]

NM_000545.8(HNF1A):c.1424C>T (p.Pro475Leu)

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.1424C>T (p.Pro475Leu)

Other names:

NM_000545.8(HNF1A):c.1424C>T

HGVS:

NC_000012.12:g.120997588C>T
NG_011731.2:g.23843C>T
NM_000545.6:c.1424C>T
NM_000545.8:c.1424C>TMANE SELECT
NM_001306179.2:c.1424C>T
NP_000536.6:p.Pro475Leu
NP_001293108.2:p.Pro475Leu
LRG_522t1:c.1424C>T
LRG_522:g.23843C>T
NC_000012.11:g.121435391C>T
NM_000545.5:c.1424C>T
NM_000545.6(HNF1A):c.1424C>T

Protein change:

P475L

Links:

dbSNP: rs193922580

NCBI 1000 Genomes Browser:

rs193922580

Molecular consequence:

NM_000545.8:c.1424C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.1424C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

Recent activity

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SRX1012818 (1)
SRA
PREDICTED: Megalobrama amblycephala fibroblast growth factor 1a (fgf1a), mRNA
PREDICTED: Megalobrama amblycephala fibroblast growth factor 1a (fgf1a), mRNA
gi|2238840494|ref|XM_048177069.1|

Nucleotide
Botryoid odontogenic cyst
Botryoid odontogenic cyst

MedGen
Gestures
Gestures
Movement of a part of the body for the purpose of communication.<br/>Year introduced: 1991(1975)

MeSH
Personality Inventory
Personality Inventory
Check list, usually to be filled out by a person about himself, consisting of many statements about personal characteristics which the subject checks.<br/>Year introduced: 1968(1966)

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001422651	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 (2) [See all records that cite these PMIDs] 23348805, 25741868 Citation Link,
SCV005201063	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications HNF1A V2.1.0)	Uncertain significance (Aug 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001422651

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

Citation Link,

SCV005201063

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications HNF1A V2.1.0)

Uncertain significance
(Aug 1, 2024)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

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

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

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

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422651.2

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

Description

The p.Pro475Leu variant in HNF1A has been reported in at least 2 individuals (including 1 Thai individual) with Monogenic Diabetes (PMID: 18811724, 23348805), and has been identified in 0.09954% (10/10046) of Ashkenazi Jewish chromosomes and 0.002659% (3/112840) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922580). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar and as a VUS in the literature (Variation ID: 36801; PMID: 27080136). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro475Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS4_Supporting (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 ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV005201063.1

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

Description

The c.1424C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 475 (p.(Pro475Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.751, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 18811724, 23674172, internal lab contributors). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2: internal lab contributors). The frequency of the c.1424C>T variant in gnomAD v2.1.1 falls between the ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.1424C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PP4, BS2.

#	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: Oct 26, 2024

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