Submissions for variant NM_000545.8(HNF1A):c.1405C>T (p.His469Tyr)

gnomAD frequency: 0.00006  dbSNP: rs201811844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000734466	SCV000862611	uncertain significance	not provided	2018-07-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000734466	SCV001146098	uncertain significance	not provided	2019-06-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001111782	SCV001269374	likely benign	Maturity-onset diabetes of the young type 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV000734466	SCV002124971	uncertain significance	not provided	2022-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 469 of the HNF1A protein (p.His469Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with early onset diabetes, as well as in control individuals (PMID: 24097065, 25555642, 27899486, 32910913). ClinVar contains an entry for this variant (Variation ID: 598142). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 27899486, 32910913). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586910	SCV005076348	likely benign	not specified	2024-04-12	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1405C>T (p.His469Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249830 control chromosomes. The observed variant frequency is approximately 5 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), strongly suggesting that the variant is benign. c.1405C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young 3. These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. Co-occurrences with a pathogenic variant has been reported (HNF1A, p.G207D), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant affects transcriptional acitivity and nuclear localization (Najmi_2017). ClinVar contains an entry for this variant (Variation ID: 598142). Based on the evidence outlined above, the variant was classified as likely benign.