Submissions for variant NM_175914.5(HNF4A):c.481A>G (p.Ser161Gly)

gnomAD frequency: 0.00001  dbSNP: rs779555087

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004568301	SCV005050187	uncertain significance	Monogenic diabetes	2024-05-09	reviewed by expert panel	curation	The c.481A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to glycine at codon 161 (p.(Ser161Gly)) of NM_175914.5. The Grpmax filtering allele frequency of the c.481A>G variant in gnomAD v2.1.1 is 0.00001121, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in an individual with a clinical history of HNF4A-MODY (diagnosed over 35 years old but clinical judgment applied due to multiple hypoglycemic episodes on sulfonylurea and negative genetic testing for HNF1A) (PP4; internal lab contributor). Additionally, this variant has a REVEL score of 0.347, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.481A>G 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): PP4.
CeGaT Center for Human Genetics Tuebingen	RCV000585597	SCV000693054	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141898	SCV001302281	uncertain significance	Familial hyperinsulinism	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001143693	SCV001304241	uncertain significance	Maturity-onset diabetes of the young type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003148800	SCV003804748	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 rs779555087 in MODY, yet.
Ambry Genetics	RCV003148800	SCV003879963	uncertain significance	Maturity onset diabetes mellitus in young	2023-02-24	criteria provided, single submitter	clinical testing	The p.S161G variant (also known as c.481A>G), located in coding exon 5 of the HNF4A gene, results from an A to G substitution at nucleotide position 481. The serine at codon 161 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.