rs886039544
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPM1_SupportingPM5_SupportingPP4_ModeratePP3
This summary comes from the ClinGen Evidence Repository: The c.779C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to arginine at codon 260 (p.(Thr260Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Arg (PM5_Supporting). In summary, c.779C>G p.Thr260Arg meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966083/MONDO:0015967/085
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.779C>G | p.Thr260Arg | missense_variant | 4/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.779C>G | p.Thr260Arg | missense_variant | 4/10 | ||
HNF1A | NM_001406915.1 | c.779C>G | p.Thr260Arg | missense_variant | 4/9 | ||
HNF1A | XM_024449168.2 | c.779C>G | p.Thr260Arg | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.779C>G | p.Thr260Arg | missense_variant | 4/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Sep 19, 2023 | The c.779C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to arginine at codon 260 (p.(Thr260Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.943, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.779C>T p.Thr260Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Thr260Arg (PM5_Supporting). In summary, c.779C>G p.Thr260Arg meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.