Variant: NM_001306179.2:c.1295C>A

CA386969822

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: e2be7ac8-b914-4c9c-8023-f7ac3eba7058

Approved on: 2023-07-30

Published on: 2023-07-30

HGVS expressions

NM_001306179.2:c.1295C>A
NC_000012.12:g.120996728C>A
CM000674.2:g.120996728C>A
NC_000012.11:g.121434531C>A
CM000674.1:g.121434531C>A
NC_000012.10:g.119918914C>A
NG_011731.2:g.22983C>A
ENST00000257555.11:c.1295C>A
ENST00000257555.10:c.1295C>A
ENST00000400024.6:c.1295C>A
ENST00000402929.5:n.1430C>A
ENST00000535955.5:n.43-763C>A
ENST00000538626.2:n.191-763C>A
ENST00000538646.5:c.*271C>A
ENST00000540108.1:c.*735C>A
ENST00000541395.5:c.1295C>A
ENST00000541924.5:c.*309C>A
ENST00000543255.1:n.339C>A
ENST00000543427.5:c.758C>A
ENST00000544413.2:c.1295C>A
ENST00000544574.5:c.*58C>A
ENST00000560968.5:n.1112C>A
ENST00000615446.4:c.83C>A
ENST00000617366.4:c.587-906C>A
NM_000545.5:c.1295C>A
NM_000545.6:c.1295C>A
NM_001306179.1:c.1295C>A
NM_000545.8:c.1295C>A

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PP4_Moderate

• Not Met criteria codes: PP1 PM5

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.1295C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to tyrosine at codon 432 (p.(p.Ser432Tyr)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.1295C>T p.Ser432Phe and c.1295C>G p.Ser432Cys, have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. 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 (PMID: 27236918, internal lab contributors). In summary, c.1295C>A 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 2.0.0, approved 1/11/2023): PP4_Moderate, PP3, PM2_Supporting.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.887, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody-negative, and sensitive to sulfonylureas) (PP4_Moderate; internal lab contributors).

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 (PMID: 27236918, internal lab contributors).
• PM5: Two other missense variants, c.1295C>T p.Ser432Phe and c.1295C>G p.Ser432Cys, have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied.