Submissions for variant NM_175914.5(HNF4A):c.1138G>A (p.Val380Ile)

gnomAD frequency: 0.00001  dbSNP: rs137853337

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004991968	SCV005442865	uncertain significance	Monogenic diabetes	2024-12-20	reviewed by expert panel	curation	The c.1138G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 380 (p.(Val380Ile)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 2 copies in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9449683, 23227446, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 9449683). This variant has a REVEL score of 0.344, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. Functional studies demonstrated the p.Val380Ile protein has abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 30191603) (BS3_Supporting). Another missense variant, [1139T>G p.(Val380Gly)] has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1138G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_moderate, PP4, PM2_supporting, BS3_supporting.
GeneDx	RCV000481825	SCV000568585	uncertain significance	not provided	2017-02-06	criteria provided, single submitter	clinical testing	The V380I variant in the HNF4A gene has been previously reported (as V393I due to the use of alternative nomenclature) in one family in association with non-insulin dependent diabetes mellitus; however, segregation of the variant with disease was equivocal, as several clinically unaffected individuals harbored the V380I variant, while the variant was absent in at least two individuals with impaired glucose tolerance (Hani et al., 1998). The V380I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V380I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Although one in vitro functional study concluded this variant results in a decrease in protein transactivation ability, additional studies are needed to validate the functional effect of this variant in vivo (Hani et al., 1998). We interpret V380I as a variant of uncertain significance, which may be related to the reported overgrowth, hypoglycemia, and hypotonia in this individual.
Fulgent Genetics, Fulgent Genetics	RCV002482848	SCV002789803	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	2022-04-23	criteria provided, single submitter	clinical testing
OMIM	RCV000009793	SCV000030014	pathogenic	Type 2 diabetes mellitus	1998-02-01	no assertion criteria provided	literature only