rs1555211436
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_ModeratePVS1PP4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.494G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 165 (p.(Trp165Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 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 is absent from gnomAD v2.1.1 (PM2_Supporting). Furthermore, this variant segregated with diabetes, with three informative meioses, in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability estimated between 39-59% based on available clinical information, sulfonylurea-sensitive, and negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.494G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Moderate, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386960529/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.494G>A | p.Trp165* | stop_gained | 2/10 | ENST00000257555.11 | NP_000536.6 | |
HNF1A | NM_001306179.2 | c.494G>A | p.Trp165* | stop_gained | 2/10 | NP_001293108.2 | ||
HNF1A | NM_001406915.1 | c.494G>A | p.Trp165* | stop_gained | 2/9 | NP_001393844.1 | ||
HNF1A | XM_024449168.2 | c.494G>A | p.Trp165* | stop_gained | 2/9 | XP_024304936.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.494G>A | p.Trp165* | stop_gained | 2/10 | 1 | NM_000545.8 | ENSP00000257555.5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jun 10, 2022 | The c.494G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 165 (p.(Trp165Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 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 is absent from gnomAD v2.1.1 (PM2_Supporting). Furthermore, this variant segregated with diabetes, with three informative meioses, in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability estimated between 39-59% based on available clinical information, sulfonylurea-sensitive, and negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.494G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting, PP1_Moderate, PP4. - |
Maturity onset diabetes mellitus in young Pathogenic:1
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. However, more evidence is required to confer the association of this particular variant rs1555211436 with MODY3. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 17, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at