Submissions for variant NM_175914.5(HNF4A):c.361A>G (p.Ser121Gly)

gnomAD frequency: 0.00006  dbSNP: rs193922472

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003234542	SCV003932650	likely benign	Monogenic diabetes	2023-05-27	reviewed by expert panel	curation	The c.361A>G variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of serine to glycine at codon 121 (p.(Ser121Gly)) in NM_175914.5. The Popmax filtering allele frequency of the c.361A>G variant in gnomAD v2.1.1 is 0.00006673, which is greater than the MDEP threshold for BS1 (0.000033) (BS1). This variant has a REVEL score of 0.555, which is between the ClinGen MDEP established cutoffs for PP3 and BS4, predicting neither a damaging nor benign impact on HNF4A function; thus, neither criterion will be applied. This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.361A>G meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BS1, BP5.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030019	SCV000052674	uncertain significance	not specified	2019-02-05	criteria provided, single submitter	clinical testing	Variant summary: The variant, HNF4A c.361A>G (p.Ser121Gly, Legacy name c.427A>G) results in a non-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. Several computational tools predict a conflicting impact on normal splicing: Three predict the variant strengthens a cryptic exonic 5' donor site. One predict the variant weakens the same cryptic exonic 5' donor site. However, these predictions have yet to be confirmed by functional studies.The variant allele was found at a frequency of 5.3e-05 in 245900 control chromosomes. The observed variant frequency is approximately 17 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), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.361A>G 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. 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 uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, the emergence of control population databases since the original classification have helped establish an allele frequency greater than expected for MODY1 (BS1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneDx	RCV000484752	SCV000574139	uncertain significance	not provided	2017-03-20	criteria provided, single submitter	clinical testing	The c.361 A>G variant in the HNF4A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.361 A>G variant is observed in 7/65226 (0.01%) alleles from individuals of European Non-Finnish background in the ExAC dataset (Lek et al., 2016). In-silico splice prediction models predict that c.361 A>G may create a cryptic splice donor site in exon 4 that could supplant the natural splice donor site. However, in the absence of RNA/functional studies, the actual effect of the c.361 A>G change in this individual is unknown. If c.361 A>G does not alter splicing, it will result in the S121G missense change. The S121G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.361 A>G as a variant of uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248909	SCV001422644	uncertain significance	Maturity onset diabetes mellitus in young	2020-01-22	criteria provided, single submitter	curation	The p.Ser143Gly variant in HNF4A has been reported in 1 individual with Maturity-Onset Diabetes of the Young in ClinVar (Variation ID: 36349), and has been identified in 0.01145% (13/113552) of European (non-Finnish) chromosomes and 0.002894% (1/34554) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922472). This variant has also been reported in an individual without diabetes (PMID: 24097065). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 36349). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ser143Gly variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV002496458	SCV002791174	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	2021-10-07	criteria provided, single submitter	clinical testing