rs137853237
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM1_SupportingPS3_SupportingPP1_Moderate
This summary comes from the ClinGen Evidence Repository: The c.395A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 122 (p.(Y122C)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and was identified in two individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9097962, internal lab contributor). The variant also segregated with diabetes with four informative meioses in one family with MODY (PP1_Moderate; PMID:9097962). Additionally, functional studies demonstrated the p.Tyr122Cys protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PMID:10585442). Another missense variant, c.364T>C (p.Tyr122His) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, this evidence supports the classification of c.365A>G as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_moderate. PP3, PM1_supporting, PM2_supporting, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124457/MONDO:0015967/017
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.365A>G | p.Tyr122Cys | missense_variant | 2/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.365A>G | p.Tyr122Cys | missense_variant | 2/10 | ||
HNF1A | NM_001406915.1 | c.365A>G | p.Tyr122Cys | missense_variant | 2/9 | ||
HNF1A | XM_024449168.2 | c.365A>G | p.Tyr122Cys | missense_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.365A>G | p.Tyr122Cys | missense_variant | 2/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 19, 2021 | The c.395A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of tyrosine to cysteine at codon 122 (p.(Y122C)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting) and was identified in two individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9097962, internal lab contributor). The variant also segregated with diabetes with four informative meioses in one family with MODY (PP1_Moderate; PMID:9097962). Additionally, functional studies demonstrated the p.Tyr122Cys protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PMID:10585442). Another missense variant, c.364T>C (p.Tyr122His) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. Taken together, this evidence supports the classification of c.365A>G as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_moderate. PP3, PM1_supporting, PM2_supporting, PS3_supporting. - |
Maturity onset diabetes mellitus in young Pathogenic:1
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 rs137853237 with MODY3. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14930). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9097962). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 122 of the HNF1A protein (p.Tyr122Cys). - |
Maturity-onset diabetes of the young type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at