NM_000545.8(HNF1A):c.527-1G>A AND Maturity onset diabetes mellitus in young

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 22, 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:: RCV002319520.2

Allele description [Variation Report for NM_000545.8(HNF1A):c.527-1G>A]

NM_000545.8(HNF1A):c.527-1G>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.527-1G>A

Other names:

NM_000545.6(HNF1A):c.527-1G>A

HGVS:

NC_000012.12:g.120993519G>A
NG_011731.2:g.19774G>A
NM_000545.8:c.527-1G>AMANE SELECT
NM_001306179.2:c.527-1G>A
NM_001406915.1:c.527-1G>A
LRG_522t1:c.527-1G>A
LRG_522:g.19774G>A
NC_000012.11:g.121431322G>A
NC_000012.11:g.121431322G>A
NM_000545.5:c.527-1G>A
NM_000545.6:c.527-1G>A

Links:

dbSNP: rs1555211904

NCBI 1000 Genomes Browser:

rs1555211904

Molecular consequence:

NM_000545.8:c.527-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001306179.2:c.527-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001406915.1:c.527-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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D009752 (1)
MeSH
Nutritional Status
Nutritional Status
State of the body in relation to the consumption and utilization of nutrients.<br/>Year introduced: 1987

MeSH
ALDH7A1 [Puma concolor]
ALDH7A1 [Puma concolor]
Gene ID:112860388

Gene
LPIN1 [Dromaius novaehollandiae]
LPIN1 [Dromaius novaehollandiae]
Gene ID:112981499

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002604973	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,
SCV004241605	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10588527, 36257325 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002604973

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,

SCV004241605

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (2)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	research

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 (6)

Details of each submission

From Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic, SCV002604973.1

#	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 rs1555211904 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241605.1

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

Description

Variant summary: HNF1A c.527-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' splice acceptor site, and two predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251006 control chromosomes (gnomAD). c.527-1G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 with evidence of cosegregation with disease (Ng_1999, Mirshahi_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10588527, 36257325). Five submitters, including a ClinGen expert panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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: Sep 29, 2024

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