ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.4del (p.Val2fs)

dbSNP: rs1555260207
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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 RCV001843360 SCV002102524 pathogenic Monogenic diabetes 2022-02-22 reviewed by expert panel curation The c. 4delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 2 (NM_000545.6), adding 4 novel amino acids before encountering a stop codon (p.(Val2PhefsTer4)). 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, the variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, 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, this 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 9/30/2021): PVS1, PM2_Supporting, PP4.
Athena Diagnostics RCV000518587 SCV000613618 pathogenic not provided 2017-02-02 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002329217 SCV002601637 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 rs1555260207 with MODY3.

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