Variant: NM_000545.6(HNF1A):c.365A>G (p.Tyr122Cys)

CA124457

14930 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 18f446a0-2192-43e6-afe0-e50751cb6115

HGVS expressions

NM_000545.6:c.365A>G
NM_000545.6(HNF1A):c.365A>G (p.Tyr122Cys)
NC_000012.12:g.120988871A>G
CM000674.2:g.120988871A>G
NC_000012.11:g.121426674A>G
CM000674.1:g.121426674A>G
NC_000012.10:g.119911057A>G
NG_011731.2:g.15126A>G
ENST00000257555.11:c.365A>G
ENST00000257555.10:c.365A>G
ENST00000400024.6:c.365A>G
ENST00000402929.5:n.500A>G
ENST00000535955.5:n.43-8620A>G
ENST00000538626.2:n.191-8620A>G
ENST00000538646.5:c.365A>G
ENST00000540108.1:c.327-4649A>G
ENST00000541395.5:c.365A>G
ENST00000541924.5:c.365A>G
ENST00000543427.5:c.365A>G
ENST00000544413.2:c.365A>G
ENST00000544574.5:c.73-7746A>G
ENST00000560968.5:n.508A>G
ENST00000615446.4:c.-257-7391A>G
ENST00000617366.4:c.365A>G
NM_000545.5:c.365A>G
NM_001306179.1:c.365A>G
NM_000545.8:c.365A>G
NM_001306179.2:c.365A>G
NM_000545.8(HNF1A):c.365A>G (p.Tyr122Cys)

Likely Pathogenic

• Met criteria codes: PS3_Supporting PP3 PM2_Supporting PP1_Moderate PM1_Supporting

• Not Met criteria codes: PP4 PM5

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

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.

Met criteria codes

• PS3_Supporting: 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)
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.977, which is greater than [or equal to] the MDEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP1_Moderate: This variant segregated with diabetes, with four informative meioses in one family with MODY (PP1_Moderate; PMID:9097962).
• PM1_Supporting: 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).

Not Met criteria codes

• PP4: This variant 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).
• PM5: Another missense variant, c.364T>C (p.Tyr122His) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2021-08-19

Published on: 2021-10-29