chr12-121001077-G-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4PP1_StrongPP3PP4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1781G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to isoleucine at codon 594 (p.(Ser594Ile)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9392505, internal lab contributors). This variant segregated with diabetes, with at least 5 informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% but antibody-negative and sulfonylurea-sensitive, negative genetic testing for HNF4A) (PP4; PMID:internal lab contributors). In summary, c.1781G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PP3, PM2_Supporting, PS4, PP1_Strong, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386940977/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1781G>T | p.Ser594Ile | missense_variant | 10/10 | ENST00000257555.11 | |
C12orf43 | NM_022895.3 | c.*3076C>A | 3_prime_UTR_variant | 6/6 | ENST00000288757.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1781G>T | p.Ser594Ile | missense_variant | 10/10 | 1 | NM_000545.8 | P4 | |
C12orf43 | ENST00000288757.7 | c.*3076C>A | 3_prime_UTR_variant | 6/6 | 1 | NM_022895.3 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726910
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 08, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11942313, 28012402, 9392505, 18003757, 28170077) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 22, 2023 | This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to segregate with disease in multiple families (personal communication related to ClinVar ID: 1315998, Accession: SCV002558822.1). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). - |
Monogenic diabetes Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Jul 01, 2022 | The c.1781G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to isoleucine at codon 594 (p.(Ser594Ile)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9392505, internal lab contributors). This variant segregated with diabetes, with at least 5 informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% but antibody-negative and sulfonylurea-sensitive, negative genetic testing for HNF4A) (PP4; PMID: internal lab contributors). In summary, c.1781G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PP3, PM2_Supporting, PS4, PP1_Strong, PP4. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Geisinger Clinic, Geisinger Health System | Aug 02, 2022 | PP3, PM2, PS4, PP1_Strong, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.