ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.186del (p.Asn62fs)

dbSNP: rs2135819908
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV002222084 SCV002499479 likely pathogenic Monogenic diabetes 2022-04-03 reviewed by expert panel curation The c.2186delT variant in the HNF1 homeobox A gene , HNF1A, causes a frameshift in the protein at codon 62 (NM_000545.8), adding 93 novel amino acids before encountering a stop codon (p.(Asn62LysfsTer93)). This variant, located in biologically-relevant exon 1 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 26431509, 27236918). The nucleotide change c.185delA, which causes the same frameshift, has been classified as pathogenic by the ClinGen MDEP; however, PS1 is not applied to frameshift variants by the ClinGen MDEP. In summary, c.186delT meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting.

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