ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.526+2dup

dbSNP: rs1555211448
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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 RCV002250371 SCV002520630 uncertain significance Monogenic diabetes 2022-04-15 reviewed by expert panel curation The c.526+2dup variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result greater than 50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.526+2dup meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PP4_Moderate, PP3.
Athena Diagnostics RCV000518513 SCV000613621 uncertain significance not specified 2017-07-05 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002319515 SCV002604981 uncertain significance 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 rs1555211448 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp RCV003727757 SCV004538202 uncertain significance not provided 2023-09-14 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 447494). This variant has not been reported in the literature in individuals affected with HNF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the HNF1A gene. It does not directly change the encoded amino acid sequence of the HNF1A protein. It affects a nucleotide within the consensus splice site.

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