Submissions for variant NM_175914.5(HNF4A):c.270C>G (p.Cys90Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004994451	SCV005442853	likely pathogenic	Monogenic diabetes	2024-11-26	reviewed by expert panel	curation	The c.270C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to tryptophan at codon 90 (p.(Cys90Trp)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). One of these individuals had a clinical picture consistent with HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative diabetes antibodies), and this variant was detected as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate, PP4_Moderate; internal lab contributors). In summary, c.270C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP3, PP4_Moderate, PM2_Supporting, PM1, PS2_Moderate.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004720201	SCV005326350	likely pathogenic	Maturity-onset diabetes of the young type 1		criteria provided, single submitter	clinical testing	The p.Cys90Trp variant results in substitution of the cysteine at amino acid position 90 with a tryptophan. The p.Cys90 position is located in one of two zinc-finger domains making up the DNA binding domain in the HNF4A protein. The cysteine at amino acid position 90 is highly conserved. In silico tools predict the p.Cys90Trp variant to be damaging. Nearby variants in the same domain, including the p.Cys93Tyr variant (ClinVar Variation ID: 2502290), have been observed among individuals with HNF4A-related diabetes. To our knowledge, the p.Cys90Trp variant is absent from patient databases and the medical literature, as well as large population studies (gnomAD v4.0.0).