Submissions for variant NM_175914.5(HNF4A):c.322G>A (p.Val108Ile)

gnomAD frequency: 0.00001  dbSNP: rs377476335

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003325993	SCV004032062	pathogenic	Monogenic diabetes	2023-08-13	reviewed by expert panel	curation	The c.322G>A variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 108 (p.(Val108Ile)) of NM_175914.5. This variant is located within the DNA binding domain (codons 80-110) of HNF4A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 1 copy in the East Asian subpopoulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.804, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 16 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID 12203996, PMID 12627330, PMID 28701371, internal lab contributors). This variant segregated with diabetes with 18 informative meioses in 3 families (PP1_Strong; PMID 12203996, 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). In summary, this evidence supports the classification of this variant as pathogenic for HNF4A-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PS4, PP1_Strong, PP4.
Athena Diagnostics	RCV001288638	SCV001475909	likely pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Conflicting predictions of the effect on the protein. Strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.
Geisinger Clinic, Geisinger Health System	RCV002285470	SCV002562161	pathogenic	Maturity-onset diabetes of the young type 1	2022-08-02	criteria provided, single submitter	research	PM1_Supporting, PM2, PP3, PS4, PP1_Strong, PP4
Ambry Genetics	RCV002447257	SCV002611397	pathogenic	Maturity onset diabetes mellitus in young	2016-05-04	criteria provided, single submitter	clinical testing	The p.V108I pathogenic mutation (also known as c.322G>A), located in coding exon 4 of the HNF4A gene, results from a G to A substitution at nucleotide position 322. The valine at codon 108 is replaced by isoleucine, an amino acid with highly similar properties. This mutation (referred to as p.V121I) was first reported in a large Swiss kindred in which the mutation co-segregated with disease (Monney CT, Hum. Mutat. 2002 Sep; 20(3):230-1). Additional MODY patients have been reported to be heterozygous for this mutation (Pruhova S, Diabetologia 2003 Feb; 46(2):291-5; Feigerlov&aacute; E, Eur. J. Pediatr. 2006 Jul; 165(7):446-52). Based on the supporting evidence, p.V108I is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002499506	SCV002816024	likely pathogenic	Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2021-08-15	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV002447257	SCV004812599	likely pathogenic	Maturity onset diabetes mellitus in young	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in HNF4A is predicted to replace valine with isoleucine at codon 108, p.(Val108Ile) (also known as p.Val121Ile). The valine residue is highly conserved (98/98 vertebrates, UCSC), and is located in the DNA binding domain (amino acids 37-113), which is defined as a critical functional domain (PMID:18829458). There is a small physicochemical difference between valine and isoleucine. This variant is present in two individuals from the European (non-Finnish) population and a single individual from the East Asian population in the population database gnomAD v2.1 and v3.1, which is consistent with HNF4A-related diabetes. This variant has been reported in at least eight probands with suspected maturity-onset diabetes of the young (MODY) and segregates with disease in at least two of these families (PMID: 12203996, 12627330, 16602010, 28701371, 34556497, 35089870, 36257325). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM1_Supporting, PM2_Supporting.