Variant: NM_000545.8(HNF1A):c.281C>T (p.Pro94Leu)

CA214295

36816 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 02411569-0b5b-4f6a-9abd-8f9cfb0e9ac9

Approved on: 2022-04-07

Published on: 2022-07-12

HGVS expressions

NM_000545.8:c.281C>T
NM_000545.8(HNF1A):c.281C>T (p.Pro94Leu)
NC_000012.12:g.120979049C>T
CM000674.2:g.120979049C>T
NC_000012.11:g.121416852C>T
CM000674.1:g.121416852C>T
NC_000012.10:g.119901235C>T
NG_011731.2:g.5304C>T
ENST00000257555.11:c.281C>T
ENST00000257555.10:c.281C>T
ENST00000400024.6:c.281C>T
ENST00000402929.5:n.416C>T
ENST00000535955.5:n.42+357C>T
ENST00000538626.2:n.190+209C>T
ENST00000538646.5:c.281C>T
ENST00000540108.1:c.281C>T
ENST00000541395.5:c.281C>T
ENST00000541924.5:c.281C>T
ENST00000543427.5:c.281C>T
ENST00000544413.2:c.281C>T
ENST00000544574.5:c.72+209C>T
ENST00000560968.5:n.424C>T
ENST00000615446.4:c.-258+338C>T
ENST00000617366.4:c.281C>T
NM_000545.5:c.281C>T
NM_000545.6:c.281C>T
NM_001306179.1:c.281C>T
NM_001306179.2:c.281C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Moderate PP3

• Not Met criteria codes: PS4 PP1

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.281C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 94 (p.(Pro94Leu)) of NM_000545.8. This variant is absent from gnomAD v.2.1.1 (PM2_supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP threshold of 0.70 (PP3). Furthermore, this variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to sulfonylurea, antibody negative and persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_supporting, PP3, PP4_Moderate.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v.2.1.1 (PM2_supporting).
• PP4_Moderate: Tthis variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, response to sulfonylurea, antibody negative and persistent C-peptide) (PP4_Moderate; [internal lab contributors]).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: Segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors).