Submissions for variant NM_175914.5(HNF4A):c.1199G>A (p.Arg400Gln)

gnomAD frequency: 0.00006  dbSNP: rs202073574

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003318509	SCV004022359	likely benign	Monogenic diabetes	2023-07-30	reviewed by expert panel	curation	The c.1199G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 400 (p.(Arg400Gln)) of NM_175914.5. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009487, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar Variation ID: 1411449, internal lab contributors). Several of these individuals have antibody-negative diabetes; however, the calculated MODY probability is <50% (internal lab contributors). Additionally, this variant is predicted to be benign by computational evidence, with a REVEL score of 0.06199, which is less than the MDEP threshold of 0.15 (BP4). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). In summary, this variant meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): BS1, BP4, BP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001942956	SCV002185679	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 400 of the HNF4A protein (p.Arg400Gln). This variant is present in population databases (rs202073574, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HNF4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1411449). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV002490264	SCV002781031	uncertain significance	Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2021-12-06	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002490264	SCV004046521	uncertain significance	Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2023-03-16	criteria provided, single submitter	clinical testing	The c.1265G>A p.(Arg422Gln) variant in the HNF4A gene has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 1411449] as a Variant of Uncertain Significance. The c.1265G>A variant is observed in 45 alleles (~0.006% minor allele frequency with 0homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1265G>A variant in HNF4A is located in exon 9 of this 10-exon gene, and predicted to replace a moderately conserved arginine amino acid with glutamine at position 422 of the encoded protein. In silico predictions are inconclusive of the variant's effect [(CADD v1.6 = 22.1, REVEL = 0.062)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.1265G>A p.(Arg422Gln) variant identified in HNF4A is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV001942956	SCV005075196	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	HNF4A: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699549	SCV005203146	likely benign	not specified	2024-07-09	criteria provided, single submitter	clinical testing	Variant summary: HNF4A c.1199G>A (p.Arg400Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250610 control chromosomes. The observed variant frequency is approximately 21 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF4A causing Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus phenotype (3.1e-06). To our knowledge, no occurrence of c.1199G>A in individuals affected with Maturity Onset Diabetes Of The Young 1/Neonatal Diabetes Mellitus and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1411449). Based on the evidence outlined above, the variant was classified as likely benign.