Variant: NM_175914.5(HNF4A):c.530T>C (p.Val177Ala)

CA409106086

1399408 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: cf557e38-1b03-483b-bc6b-f0149c68fd17

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_175914.5:c.530T>C
NM_175914.5(HNF4A):c.530T>C (p.Val177Ala)
NC_000020.11:g.44414610T>C
CM000682.2:g.44414610T>C
NC_000020.10:g.43043250T>C
CM000682.1:g.43043250T>C
NC_000020.9:g.42476664T>C
NG_009818.1:g.63810T>C
ENST00000316673.9:c.530T>C
ENST00000316099.10:c.596T>C
ENST00000619550.5:c.570T>C
ENST00000683148.1:n.572T>C
ENST00000683657.1:n.1720T>C
ENST00000316099.9:c.596T>C
ENST00000316099.8:c.596T>C
ENST00000316673.8:c.530T>C
ENST00000372920.1:c.*363T>C
ENST00000415691.2:c.596T>C
ENST00000443598.6:c.596T>C
ENST00000457232.5:c.530T>C
ENST00000609795.5:c.530T>C
ENST00000619550.4:c.521T>C
NM_000457.4:c.596T>C
NM_001030003.2:c.530T>C
NM_001030004.2:c.530T>C
NM_001258355.1:c.575T>C
NM_001287182.1:c.521T>C
NM_001287183.1:c.521T>C
NM_001287184.1:c.521T>C
NM_175914.4:c.530T>C
NM_178849.2:c.596T>C
NM_178850.2:c.596T>C
NM_001030003.3:c.530T>C
NM_001030004.3:c.530T>C
NM_001258355.2:c.575T>C
NM_001287182.2:c.521T>C
NM_001287184.2:c.521T>C
NM_178849.3:c.596T>C
NM_178850.3:c.596T>C
NM_000457.5:c.596T>C
NM_000457.6:c.596T>C
NM_001287183.2:c.521T>C

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting PP4_Moderate

• Not Met criteria codes: PS4 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 for HNF4A Version 2.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.530T>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of valine to alanine at codon 177 (p.(Val177Ala)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 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 (PMID: 27420379, internal lab contributors). Two of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody-negative or SU-sensitive) (PP4_Moderate; PMID: 27420379, 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 (internal lab contributors). Another missense variant, c.530T>A p.Val177Asp, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.530T>C 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 10/11/2023): PP4_Moderate, PP3, PM2_Supporting.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). v4.1 GrpMax FAF = 0 (1 copy)
• PP4_Moderate: This variant was identified in 2 with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody-negative or SU-sensitive) (PP4_Moderate; PMID: 27420379, internal lab contributors).

Not Met criteria codes

• PS4: This variant was identified in 3 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 (PMID: 27420379, internal lab contributors).
• PP1: 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 (internal lab contributors).
• PM5: Another missense variant, c.530T>A p.Val177Asp, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.