Submissions for variant NM_175914.5(HNF4A):c.994C>T (p.Gln332Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004798504	SCV005420268	likely pathogenic	Monogenic diabetes	2024-12-02	reviewed by expert panel	curation	The c.994C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, results in a premature termination at codon 332 (p.(Gln332Ter)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant, located in biologically-relevant exon 8 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PP4 cannot be applied because of limited clinical information (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.994C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): PVS1, PM2_Supporting.
GeneDx	RCV004798503	SCV005419982	pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Reported in a family with maturity-onset diabetes of the young in the literature, although additional clinical information and familial segregation data were not provided (PMID: 23348805); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348805)