Submissions for variant NM_000545.8(HNF1A):c.1380_1406del (p.Gln460_Leu468del)

dbSNP: rs544842497

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001326514	SCV001517546	uncertain significance	not provided	2022-04-25	criteria provided, single submitter	clinical testing	This variant, c.1380_1406del, results in the deletion of 9 amino acid(s) of the HNF1A protein (p.Gln460_Leu468del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs544842497, gnomAD 0.03%). 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: 1026109). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001326514	SCV002012920	uncertain significance	not provided	2019-05-13	criteria provided, single submitter	clinical testing	In-frame deletion of 9 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319699	SCV002604919	likely benign	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 rs544842497 with MODY3.
Ambry Genetics	RCV002319699	SCV002696454	uncertain significance	Maturity onset diabetes mellitus in young	2017-02-06	criteria provided, single submitter	clinical testing	The c.1380_1406del27 variant (also known as p.Q460_L468del) is located in coding exon 7 of the HNF1A gene. This variant results from an in-frame deletion of 27 nucleotides at positions 1380 to 1046. This results in the deletion of 9 residues between codons 460 and 468. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
New York Genome Center	RCV003227959	SCV003925175	uncertain significance	Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus	2022-03-01	criteria provided, single submitter	clinical testing	The c.1380_1406del variant identified in the HNF1A gene results in an in-frame deletion of 9 amino acids (p.Gln460_Leu468del) in the transactivation domain of the HNF1A protein (PMID: 26853433) and is expected to preserve the integrity of the reading frame. This variant has not been reported in affected individuals in the literature. The variant has 0.0002299 allele frequency in the gnomAD (v3.1.2) database (35 out of 152244 heterozygous alleles, no homozygotes) and 0.00005597 allele frequency in the gnomAD (v2.1.1) database (14 out of 250142 heterozygous alleles, no homozygotes). This variant is reported as a variant of uncertain significance in the ClinVar database (Variation ID: 1026109). Based on the available evidence, the heterozygous c.1380_1406del (p.Gln460_Leu468del) variant identified in the HNF1A gene is reported as a Variant of Uncertain Significance.
Genetic Services Laboratory, University of Chicago	RCV003151302	SCV003839584	uncertain significance	not specified	2022-06-22	no assertion criteria provided	clinical testing	DNA sequence analysis of the HNF1A demonstrated a 27 base pair deletion in exon 7, c.1380_1406del. This in-frame deletion is predicted to result in the deletion of nine amino acid residues, p.Gln460_Leu468del. This deletion does not appear to have been previously described in individuals with HNF1A-related disorders. This deletion has been described in the gnomAD database with a frequency of 0.035% in the Latino/Admixed American subpopulation (dbSNP rs544842497). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined.