ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.404del (p.Asp135fs)

dbSNP: rs2135832632
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002274266 SCV002558820 pathogenic Monogenic diabetes 2022-07-01 reviewed by expert panel curation The c.404del variant in the HNF1 Homeobox A gene, HMF1A, causes a frameshift in the protein at codon 135 (NM_000545.8), adding 20 novel amino acids before encountering a stop codon (p.(Asp135ValfsTer20)). 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: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30269055, internal lab contributors). At least one of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate; PMID 30269055, internal lab contributor). This variant also segregated with diabetes, with at least 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributor). In summary, the c.404del variant 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 9/30/21): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting.
Genetics and Molecular Pathology, SA Pathology RCV002466752 SCV002761915 likely pathogenic Maturity-onset diabetes of the young type 3 2021-10-07 criteria provided, single submitter clinical testing

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