Variant: NM_000545.6(HNF1A):c.790G>T (p.Val264Phe)

CA214327

36830 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 9700d1bf-b8e1-4a24-a0e2-79487ca358fe

HGVS expressions

NM_000545.6:c.790G>T
NM_000545.6(HNF1A):c.790G>T (p.Val264Phe)
NC_000012.12:g.120994240G>T
CM000674.2:g.120994240G>T
NC_000012.11:g.121432043G>T
CM000674.1:g.121432043G>T
NC_000012.10:g.119916426G>T
NG_011731.2:g.20495G>T
ENST00000257555.11:c.790G>T
ENST00000257555.10:c.790G>T
ENST00000400024.6:c.790G>T
ENST00000402929.5:n.925G>T
ENST00000535955.5:n.43-3251G>T
ENST00000538626.2:n.191-3251G>T
ENST00000538646.5:c.603G>T
ENST00000540108.1:c.*230G>T
ENST00000541395.5:c.790G>T
ENST00000541924.5:c.713+534G>T
ENST00000543427.5:c.633+614G>T
ENST00000544413.2:c.790G>T
ENST00000544574.5:c.73-2377G>T
ENST00000560968.5:n.893+40G>T
ENST00000615446.4:c.-257-2022G>T
ENST00000617366.4:c.586+661G>T
NM_000545.5:c.790G>T
NM_001306179.1:c.790G>T
NM_000545.8:c.790G>T
NM_001306179.2:c.790G>T
NM_000545.8(HNF1A):c.790G>T (p.Val264Phe)

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PP3 PM1

• Not Met criteria codes: PP1 PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.790G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to phenylalanine at codon 264 (p.(Val264Phe)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and low renal glucose threshold in one) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.790G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PM1, PM2_Supporting, PP3, PP4_Moderate.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• PP4_Moderate: This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, one case with low renal glucose theshold).
• PP3: REVEL 0.964 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.84
• PM1: This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP.

Not Met criteria codes

• PP1: This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).
• PS4: This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).

Approved on: 2022-04-14

Published on: 2022-07-12