Submissions for variant NM_000545.8(HNF1A):c.1330_1331del (p.Gln444fs)

dbSNP: rs776793516

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Translational Genomics Laboratory, University of Maryland School of Medicine	RCV000754812	SCV000882462	pathogenic	Maturity-onset diabetes of the young type 3	2018-04-17	criteria provided, single submitter	clinical testing	The c.1328_1329delCA variant in the HNF1A homeobox A gene, HNF1A, results in a frame shifting change in the protein with the Glutamine at codon 444 (exon 7) being the first affected amino acid. Frameshift mutations in the HNF1A gene, including ones in exon 7, have been reported previously in patients with a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 3 (MODY3) (23348805, 9439666, 11272211, 18003757). The c.1328_1329delCA variant has been previously identified in multiple individuals with MODY3 (9439666, 11272211, 25414397, 9075818, 12453976), with evidence of familial segregation in three families (11272211, 9075818, 12453976). This result is also consistent with the clinical diagnosis of MODY in multiple paternal family members. ACMG criteria = PVS1, PS4-mod, PP1-mod
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000754812	SCV001422860	pathogenic	Maturity-onset diabetes of the young type 3	2020-01-22	criteria provided, single submitter	curation	The p.Gln444Glufs variant in HNF1a has been reported in 5 families with maturity-onset diabetes of the young type 3 (MODY3) and has been identified in 0.0008888% (1/112510) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs776793516). This variant has also been reported in ClinVar (VariationID: 617650) as pathogenic by the Translational Genomics Laboratory. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 444 and leads to a premature termination codon 104 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in MODY3. In summary, this variant meets criteria to be classified as pathogenic for MODY3 in an autosomal dominant manner based on the prediction that it causes loss of function of the HNF1A gene and the increased prevalence of the variant in affected individuals compared with controls. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855856	SCV002238287	pathogenic	not provided	2022-09-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant is also known as A443fsdelCA. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9439666, 25414397). This variant is present in population databases (rs776793516, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln444Glufs*104) 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).
Geisinger Clinic, Geisinger Health System	RCV000754812	SCV002562122	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PVS1, PM2, PP4_Moderate, PS4_Moderate, PP1
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002386312	SCV002601584	likely risk allele	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 rs776793516 with MODY3.
Ambry Genetics	RCV002386312	SCV002692293	pathogenic	Maturity onset diabetes mellitus in young	2020-11-30	criteria provided, single submitter	clinical testing	The c.1330_1331delCA pathogenic mutation, located in coding exon 7 of the HNF1A gene, results from a deletion of two nucleotides at nucleotide positions 1330 to 1331, causing a translational frameshift with a predicted alternate stop codon (p.Q444Efs*104). This mutation has been identified in families with maturity onset diabetes of the young (Frayling TM et al. Hum. Genet., 1997 Dec;101:351-4; Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV001855856	SCV002770272	pathogenic	not provided	2022-12-22	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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9439666, 23348805, 18003757, 11272211, 9075818, 12453976, 34789499, 25414397)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002386312	SCV004848477	pathogenic	Maturity onset diabetes mellitus in young	2020-11-06	criteria provided, single submitter	clinical testing	The p.Gln444GlufsX104 variant in HNF1A has been reported in at least 3 families with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 13 affected relatives from 2 families (Frayling 1997 PMID: 9439666, Frayling 2001 PMID: 11272211, Delvecchio 2014 PMID: 25414397, Frayling 1997 PMID: 9075818, Klupa 2002 PMID: 12453976). This variant has also been reported in ClinVar (Variation ID 617650) and identified in 1/112510 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 444 and leads to a premature termination codon 104 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant MODY. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PM2, PVS1, PS4_Supporting, PP1_Strong.