Submissions for variant NM_000545.8(HNF1A):c.1489C>T (p.Gln497Ter)

dbSNP: rs1555212396

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810462	SCV002059991	pathogenic	Monogenic diabetes	2021-12-31	reviewed by expert panel	curation	The c.1489C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 497 (p.(Gln497Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 7 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% (45.5%), but negative genetic testing for HNF4A and an extreme response to low dose sulfonylurea) (PP4; internal lab contributors). In summary, c.1489C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PP4_Supporting.
GeneDx	RCV000579156	SCV000681307	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing	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 in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Athena Diagnostics	RCV000579156	SCV001146100	pathogenic	not provided	2019-01-10	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002330997	SCV002601615	pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs1555212396 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000579156	SCV005829269	pathogenic	not provided	2024-02-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln497*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 489311). For these reasons, this variant has been classified as Pathogenic.