Submissions for variant NM_175914.5(HNF4A):c.2T>C (p.Met1Thr)

dbSNP: rs1229650809

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003493749	SCV004242369	likely pathogenic	Monogenic diabetes	2024-01-02	reviewed by expert panel	curation	The c.2T>C variant in the hepatic nuclear factor-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF <= 1:333,000 (<= 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND <= 2 copies observed in ENF AND <= 1 copy in any other founder or non-founder population) (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.2T>C 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): PVS1_Strong, PS4_Moderate, PM2_Supporting.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000850387	SCV000992574	uncertain significance	Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young	2019-07-01	criteria provided, single submitter	research	ACMG codes: PVS1
GeneDx	RCV001759638	SCV001996322	uncertain significance	not provided	2019-10-02	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001759638	SCV002301126	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the HNF4A mRNA. The next in-frame methionine is located at codon 71. This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 21683639, 30977832). ClinVar contains an entry for this variant (Variation ID: 689636). This variant disrupts a region of the HNF4A protein in which other variant(s) (p.Arg63Trp) have been determined to be pathogenic (PMID: 20164212, 25819479, 28458902, 31875549). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV003148886	SCV003804446	uncertain risk allele	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs1229650809 in MODY, yet.