ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.1129del (p.Leu377fs)

dbSNP: rs193922576
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV001810403 SCV002059986 pathogenic Monogenic diabetes 2021-12-31 reviewed by expert panel curation The c.1129delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 377 (NM_000545.8), adding 7 novel amino acids before encountering a stop codon (p.(Leu377SerfsTer7)). This variant, located in biologically-relevant exon 6 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). Also, 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). In summary, c.1129delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): PVS1, PP4, PM2_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030476 SCV000053146 likely pathogenic Maturity-onset diabetes of the young type 3 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV001852601 SCV002203263 pathogenic not provided 2020-12-10 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 23348805). ClinVar contains an entry for this variant (Variation ID: 36796). This sequence change creates a premature translational stop signal (p.Leu377Serfs*7) 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).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002326696 SCV002601613 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. However, more evidence is required to confer the association of this particular variant rs193922576 with MODY3.

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