Variant: NM_000545.6(HNF1A):c.475C>T (p.Arg159Trp)

CA244529794

429750 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: cb08fbb4-f6a7-453e-8d69-a7c412e82e90

HGVS expressions

NM_000545.6:c.475C>T
NM_000545.6(HNF1A):c.475C>T (p.Arg159Trp)
NC_000012.12:g.120988981C>T
CM000674.2:g.120988981C>T
NC_000012.11:g.121426784C>T
CM000674.1:g.121426784C>T
NC_000012.10:g.119911167C>T
NG_011731.2:g.15236C>T
ENST00000257555.11:c.475C>T
ENST00000257555.10:c.475C>T
ENST00000400024.6:c.475C>T
ENST00000402929.5:n.610C>T
ENST00000535955.5:n.43-8510C>T
ENST00000538626.2:n.191-8510C>T
ENST00000538646.5:c.475C>T
ENST00000540108.1:c.327-4539C>T
ENST00000541395.5:c.475C>T
ENST00000541924.5:c.475C>T
ENST00000543427.5:c.475C>T
ENST00000544413.2:c.475C>T
ENST00000544574.5:c.73-7636C>T
ENST00000560968.5:n.618C>T
ENST00000615446.4:c.-257-7281C>T
ENST00000617366.4:c.475C>T
NM_000545.5:c.475C>T
NM_001306179.1:c.475C>T
NM_000545.8:c.475C>T
NM_001306179.2:c.475C>T
NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)

Pathogenic

• Met criteria codes: PM5 PM1 PM2_Supporting PS4 PP1_Strong PP4 PP3

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.475C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 159 (p.(Arg159Trp)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in multiple individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.476G>A, p.(Arg159Gln), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg159Trp has an equal or greater Grantham distance. (PM5). This variant was identified in thirteen unrelated families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; [internal lab contributors; Exeter, BMRC, Paris]). Lastly, this variant segregated with diabetes, with eight informative meioses in five families with MODY (PP1_Strong; [internal lab contributors; Exeter]). In summary, c.475C>T meets the criteria to be classified as pathogneic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5, PS4, PP1_Strong.

Met criteria codes

• PM5: Another missense variant, c.476G>A, p.(Arg159Gln), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg159Trp has an equal or greater Grantham distance.
• PM1: 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.
• PM2_Supporting: This variant is absent from the gnomAD European non-Finnish population and only one copy is present in the Latino population.
• PS4: This variant was identified in greater than seven unrelated occurrences of MODY.
• PP1_Strong: This variant segregated with disease in eight informative meioses in five families with MODY.
• PP4: This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.907, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3).

Approved on: 2021-12-22

Published on: 2021-12-22