ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.472A>T (p.Lys158Ter)

dbSNP: rs2135832792
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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 RCV005054376 SCV005687823 pathogenic Monogenic diabetes 2025-01-29 reviewed by expert panel curation The c.472A>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 158 (p.Lys158Ter) of NM_000545.8. This variant, located in biologically relevant exon 2 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: 16917892). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes. Still, it did not meet the thresholds set for PS4_Moderate by the ClinGen MDEP. However, in one of the identified individuals, the MODY probability was >50% in the presence of negative HNF4A testing and negative autoantibodies (PP4_Moderate, internal lab contributors ). Only 1 informative meiosis was identified in a family, which does not meet the threshold set for PP1 by the ClinGen MDEP. In summary, c.472A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.1.1, approved 8/11/2023): PVS1, PP4_Moderate PM2_Supporting.
Genetic Services Laboratory, University of Chicago RCV001817827 SCV002069278 pathogenic not provided 2018-10-26 criteria provided, single submitter clinical testing DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.472A>T in exon 2, which results in the creation of a premature stop codon at amino acid position 158, p.Lys158*. This pathogenic sequence change is predicted to cause loss of normal protein function either through protein truncation of non-sense mediated mRNA decay. This sequence change has previously been described in a patient with HNF1A-MODY (PMID: 16917892).
Labcorp Genetics (formerly Invitae), Labcorp RCV001817827 SCV004295428 pathogenic not provided 2023-04-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1338456). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 16917892). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys158*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757).

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