rs762703502
Variant summary
Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePVS1
This summary comes from the ClinGen Evidence Repository: The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831842/MONDO:0015967/017
Frequency
Consequence
ENST00000257555.11 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.864del | p.Pro291GlnfsTer51 | frameshift_variant | 4/10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.864del | p.Pro291GlnfsTer51 | frameshift_variant | 4/10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.864del | p.Pro291GlnfsTer51 | frameshift_variant | 4/9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.864del | p.Pro291GlnfsTer51 | frameshift_variant | 4/9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.864del | p.Pro291GlnfsTer51 | frameshift_variant | 4/10 | 1 | NM_000545.8 | ENSP00000257555 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152210Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome AF: 0.00000961 AC: 14AN: 1457192Hom.: 0 Cov.: 33 AF XY: 0.0000152 AC XY: 11AN XY: 724646
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 06, 2020 | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2023 | 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: 9313763, 17054605, 30476138, 26287533, 33535453, 34587721, 35112188, 25414397) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | This sequence change creates a premature translational stop signal (p.Pro291Glnfs*51) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 26287533). ClinVar contains an entry for this variant (Variation ID: 435424). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 23, 2016 | - - |
Maturity onset diabetes mellitus in young Pathogenic:3
Likely pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | 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. Sufficient evidence is found to confer the association of this particular variant rs762703502 with MODY3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2018 | The c.864delG pathogenic mutation, located in coding exon 4 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 864, causing a translational frameshift with a predicted alternate stop codon (p.P291Qfs*51). This alteration was reported in one individual with diabetes and a family history of early-onset diabetes (Ludovico O et al. PLoS ONE, 2015 Aug;10:e0135855). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 06, 2020 | The p.Pro291GlnfsX51 variant in HNF1A has been reported in 2 individuals with monogenic diabetes (Delvecchio 2014 PMID: 25414397, Ludovico 2015 PMID: 26287533) and has also been reported in ClinVar (Variation ID: 435424). It has been identified in 0.01% (2/13784) of African chromosomes and 0.01% (8/101808) 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 291 and leads to a premature termination codon 51 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 maturity onset diabetes of the young (MODY). In summary although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PS4_Supporting. Please note, this site fails multiple random filters in exomes in gnomAD and is at a multiallelic site; therefore, follow-up Sanger analysis is recommended for exome data. - |
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Dec 30, 2021 | The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 08, 2016 | - - |
HNF1A-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 04, 2024 | The HNF1A c.864delG variant is predicted to result in a frameshift and premature protein termination (p.Pro291Glnfs*51). This variant has been reported in individuals with diabetes mellitus or Maturity-Onset Diabetes of the Young (MODY) (e.g., Wheeler et al. 2013. PubMed ID: 24355479; Ludovico et al. 2015. PubMed ID: 26287533; Yalçıntepe et al. 2021. PubMed ID: 33565752). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/435424). Frameshift and other loss-of-function variants in HNF1A are expected to be pathogenic. Based on the collective evidence, this variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at