ClinVar

Description

Variant summary: HNF1A c.1424C>T (p.Pro475Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250026 control chromosomes (gnomAD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), suggesting that the variant may be benign. c.1424C>T has been reported in the literature in several individuals affected with diabetes (e.g., Plengvidhya_2009, Billings_2022), however without strong evidence for causality (e.g., lack of co-segregation data) in all cases. The variant was also identified in several unaffected control individuals (e.g., Billings_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in moderate defects in BCL2L1 transactivation (approx. 28% reduction relative to wildtype) as well as defects in regulation of cell cycle transitions (e.g., Sujjitjoon_2020). The following publications have been ascertained in the context of this evaluation (PMID: 36208030, 18811724, 32684311). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: three submitters classified the variant as VUS, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.