NM_000545.8(HNF1A):c.1501+1G>A AND Maturity onset diabetes mellitus in young

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Nov 3, 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:: RCV002319506.4

Allele description [Variation Report for NM_000545.8(HNF1A):c.1501+1G>A]

NM_000545.8(HNF1A):c.1501+1G>A

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.1501+1G>A

Other names:

NM_000545.6(HNF1A):c.1501+1G>A

HGVS:

NC_000012.12:g.120997666G>A
NG_011731.2:g.23921G>A
NM_000545.8:c.1501+1G>AMANE SELECT
NM_001306179.2:c.1501+1G>A
NM_001406915.1:c.1309+924G>A
LRG_522:g.23921G>A
NC_000012.11:g.121435469G>A
NM_000545.6:c.1501+1G>A

Links:

dbSNP: rs1131692182

NCBI 1000 Genomes Browser:

rs1131692182

Molecular consequence:

NM_001406915.1:c.1309+924G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000545.8:c.1501+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001306179.2:c.1501+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002604936	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)	Likely pathogenic	unknown	research	PubMed (4) [See all records that cite these PMIDs] 31517624, 32395877, 35328643, 35673428 Citation Link,
SCV004848782	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 31447099, 19169489, 23348805, 28012402, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002604936

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

criteria provided, single submitter

(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)

Likely pathogenic

unknown

research

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV004848782

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 3, 2022)

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel insights into genetics and clinics of the HNF1A-MODY.

Valkovicova T, Skopkova M, Stanik J, Gasperikova D.

Endocr Regul. 2019 Apr 1;53(2):110-134. doi: 10.2478/enr-2019-0013. Review.

PubMed [citation]

PMID:: 31517624

Altered cortisol metabolism in individuals with HNF1A-MODY.

Juszczak A, Gilligan LC, Hughes BA, Hassan-Smith ZK, McCarthy MI, Arlt W, Tomlinson JW, Owen KR.

Clin Endocrinol (Oxf). 2020 Sep;93(3):269-279. doi: 10.1111/cen.14218. Epub 2020 Jun 5.

PubMed [citation]

PMID:: 32395877

See all PubMed Citations (9)

Details of each submission

From Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic, SCV002604936.1

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

Description

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1131692182 with MODY3.

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848782.1

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

Description

The c.1501+1G>A variant in HNF1A has not been reported in individuals with diabetes. This variant was classified as Likely Pathogenic on April 16, 2022 by the ClinGen-approved ClinGen Monogenic Diabetes Variant Curation Expert Panel (Variation ID 430837) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein.The c.1501+1G>T and c.1501+G>C variants in HNF1A, which are predicted to have similar effect on splicing, have been previously identified in individuals with maturity onset diabetes of the young (Maraschin 2008 PMID: 19169489, Coclough 2013 PMID: 23348805). Loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant maturity onset diabetes of the young. 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 maturity onset diabetes of the young. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

#	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: Nov 3, 2024

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