Submissions for variant NM_000545.8(HNF1A):c.1501+1G>A

dbSNP: rs1131692182

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002250367	SCV002520674	likely pathogenic	Monogenic diabetes	2022-04-16	reviewed by expert panel	curation	The c.1501+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 7 of NM_000545.8. This variant is predicted to cause an in-frame deletion of biologically-relevant exon 7 of 10, removing more than 18% of the transactivation domain, a region important for protein function (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). The nucleotide change, c.1501+1G>T, which causes the same splice donor loss, has been reported in a patient with monogenic diabetes; however, the c.1501+1G>T variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. In summary, c.1501+1G>A 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 1.1, approved 9/30/2021): PVS1, PM2_Supporting.
Institute of Endocrinology, Diabetes & Metabolism, Max Healthcare Institute Ltd.	RCV000495949	SCV000583599	likely pathogenic	Maturity-onset diabetes of the young type 3	2017-06-30	criteria provided, single submitter	research	The identified heterozygous variant (c.1501+1G>A) lies in an essential splice donor site downstream of exon 7 of the HNF1A gene. In silico splice prediction tools (NNSPLICE and ASSP) predict that this variant is likely to disrupt the splice site at the junction of exon 7 and intron 7 of the HNF1A gene. This could lead to a frameshift, which will probably result in truncation of the protein. Moreover, due to introduction of premature stop codon, this aberrant transcript will likely be targeted by nonsense mediated mRNA decay (NMD) mechanism. The identified variant seems to be a novel, as it has not been previously reported in literature nor previously identified by our laboratory. However, another splice site variant occurring at the same position as that of the identified variant, c.1501+1G>T has been previously reported in a South-Brazilian patient affected with MODY and was predicted abolish the splice donor site resulting in the generation of abnormal transcripts [PMID: 19169489]. The identified variant disrupts an essential splice site and is likely to result in a truncated protein. In addition, it lies in the vicinity of other variants associated with MODY. Thus, it has been labelled as 'likely pathogenic' (likely disease-causing).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319506	SCV002604936	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 rs1131692182 with MODY3.
Fulgent Genetics, Fulgent Genetics	RCV002475980	SCV002785200	pathogenic	Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma	2021-09-09	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002319506	SCV004848782	likely pathogenic	Maturity onset diabetes mellitus in young	2022-11-03	criteria provided, single submitter	clinical testing	The c.1501+1G>A variant in HNF1A has not been reported in individuals with diabetes. This variant was classified as Likely Pathogenic on April 16, 2022 by the ClinGen-approved ClinGen Monogenic Diabetes Variant Curation Expert Panel (Variation ID 430837) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein.The c.1501+1G>T and c.1501+G>C variants in HNF1A, which are predicted to have similar effect on splicing, have been previously identified in individuals with maturity onset diabetes of the young (Maraschin 2008 PMID: 19169489, Coclough 2013 PMID: 23348805). Loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant maturity onset diabetes of the young. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant maturity onset diabetes of the young. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.