ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.748C>T (p.Gln250Ter)

dbSNP: rs1308016430
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV001810500 SCV002059978 pathogenic Monogenic diabetes 2021-12-30 reviewed by expert panel curation The c.748C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 250 (p.(Gln250Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate, internal lab contributors). Lastly, this variant was identified in unrelated individuals from four different families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 1244228, internal lab contributors). In summary, c.748C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PP4_Moderate, PS4_Moderate.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248892 SCV001422573 likely pathogenic Maturity-onset diabetes of the young type 3 2020-01-22 criteria provided, single submitter curation The p.Gln250Ter variant in HNF1A has been reported in at least 1 individual with maturity-onset diabetes of the young (PMID: 12442280), and has been identified in 0.0009% (1/112846) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1308016430). 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 nonsense variant leads to a premature termination codon at position 250, 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 maturity-onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002464418 SCV002605531 likely pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter research 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. Sufficient evidence is found to confer the association of this particular variant rs1308016430 with MODY3.

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