Submissions for variant NM_175914.5(HNF4A):c.470AGA[1] (p.Lys158del)

dbSNP: rs1280663753

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004568633	SCV005050186	uncertain significance	Monogenic diabetes	2024-05-09	reviewed by expert panel	curation	The c.473_475del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 158 (p.(Lys158del)) within exon 5 of NM_174914.5. The c.473_475del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.473_475del 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 2.0.0, approved 10/11/2023): PM2_Supporting, PM4_Supporting.
Genetic Services Laboratory, University of Chicago	RCV000501220	SCV000595153	likely pathogenic	Maturity-onset diabetes of the young type 1	2017-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222538	SCV002500525	likely pathogenic	Maturity onset diabetes mellitus in young	2022-03-19	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.473_475delAGA (p.Lys158del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251470 control chromosomes. c.473_475delAGA has been reported in the literature as an assumed de-novo variant in at-least one 16 year old individual affected with Maturity Onset Diabetes Of The Young 1 who underwent analysis for 7 prominent MODY genes and exhibited characteristic elevations in fasting glucose and Hemoglobin A1c levels (example, Ozdemir_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002222538	SCV003804745	uncertain risk allele	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1280663753 in MODY, yet.