Submissions for variant NM_000545.8(HNF1A):c.1137del (p.Val380fs)

dbSNP: rs1555212248

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810452	SCV002059987	pathogenic	Monogenic diabetes	2021-12-31	reviewed by expert panel	curation	The c.1137del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.Val380SerfsTer4). This variant, located in biologically-relevant exon 6 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). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 33538814, internal lab contributors). This variant also segregated with diabetes, with 5 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1137del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong
Genetic Services Laboratory, University of Chicago	RCV000501374	SCV000595139	pathogenic	Maturity-onset diabetes of the young type 3	2016-06-08	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000518541	SCV000613595	pathogenic	not provided	2020-10-29	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
GeneDx	RCV000518541	SCV000748401	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	Frameshift 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: 9754819, 33852230, 25555642, 15928245, 11058894, 35089870, 34789499, 35328643, 36227502, 36257325, 9075819)
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000677301	SCV000803366	pathogenic	Maturity onset diabetes mellitus in young	2018-07-30	criteria provided, single submitter	clinical testing	The c.1137delT (p.Val380Serfs*4) pathogenic variant is located in exon 6 of the HNF1A gene. The deletion of one nucleotide causes a translational frameshift. The first amino acid altered is at position 380 of the protein, in which serine replaces valine, and there is a premature stop codon 4 amino acids downstream of this altered amino acid. This variant has been reported as pathogenic in the literature by our lab (PMID: 25555642) and others (PMID: 9075819). This variant has not been observed in the general population despite 245,334 alleles being tested (Genome Aggregation Database). Heterozygous inactivating variants in HNF1A are well-described in the medical literature and account for 30-65% of patients with a MODY phenotype (https://www.ncbi.nlm.nih.gov/books/NBK500456/). In summary, this variant is interpreted as pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000677301	SCV002600907	likely 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 rs1555212248 with MODY3.
Ambry Genetics	RCV000677301	SCV002607225	pathogenic	Maturity onset diabetes mellitus in young	2016-04-06	criteria provided, single submitter	clinical testing	The c.1137delT pathogenic mutation, located in coding exon 6 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 1137, causing a translational frameshift with a predicted alternate stop codon (p.V380Sfs*4). This mutation, referred to as P379fsdelT, was first reported in a Danish MODY family (Hansen T, Diabetes 1997 Apr; 46(4):726-30) and has also been reported in a French MODY family (Chèvre JC, Diabetologia 1998 Sep; 41(9):1017-2.3). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518541	SCV003500513	pathogenic	not provided	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val380Serfs*4) 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 premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9075819). ClinVar contains an entry for this variant (Variation ID: 435426). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003403166	SCV004104091	pathogenic	HNF1A-related disorder	2023-05-18	criteria provided, single submitter	clinical testing	The HNF1A c.1137delT variant is predicted to result in a frameshift and premature protein termination (p.Val380Serfs*4). This variant has been reported to be pathogenic for maturity onset diabetes of the young (MODY) (Pro379fs in M2 Pedigree at Hansen et al. 1997. PubMed ID: 9075819). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in HNF1A are expected to be pathogenic. This variant is interpreted as pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000501374	SCV005326345	pathogenic	Maturity-onset diabetes of the young type 3		criteria provided, single submitter	clinical testing	The p.Val380Serfs*4 variant leads to a frameshift followed by a premature termination codon after four amino acids. The variant falls within exon 6 of 10 total exons and is predicted to cause loss-of-function. This variant has been reported in multiple unrelated individuals with HNF1A-related MODY (PMID: 9075819, PMID: 33852230, PMID: 36227502, PMID: 36257325). The p.Val380Serfs*4 variant is absent from large population studies (gnomAD v2.1.1). Loss-of-function is a known pathogenic mechanism of HNF1A-related MODY.