Variant: NM_175914.5:c.194G>A

CA409103960

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 93b8638a-8aff-4a25-a7db-ce1933ee6296

HGVS expressions

NM_175914.5:c.194G>A
NC_000020.11:g.44406202G>A
CM000682.2:g.44406202G>A
NC_000020.10:g.43034842G>A
CM000682.1:g.43034842G>A
NC_000020.9:g.42468256G>A
NG_009818.1:g.55402G>A
ENST00000316673.9:c.194G>A
ENST00000316099.10:c.260G>A
ENST00000619550.5:c.234G>A
ENST00000681977.1:c.236G>A
ENST00000682169.1:c.213G>A
ENST00000683148.1:n.236G>A
ENST00000683657.1:n.236G>A
ENST00000684046.1:c.236G>A
ENST00000684136.1:c.236G>A
ENST00000684476.1:c.217G>A
ENST00000316099.9:c.260G>A
ENST00000316099.8:c.260G>A
ENST00000316673.8:c.194G>A
ENST00000372920.1:c.*27G>A
ENST00000415691.2:c.260G>A
ENST00000443598.6:c.260G>A
ENST00000457232.5:c.194G>A
ENST00000609262.5:c.185G>A
ENST00000609795.5:c.194G>A
ENST00000619550.4:c.185G>A
NM_000457.4:c.260G>A
NM_001030003.2:c.194G>A
NM_001030004.2:c.194G>A
NM_001258355.1:c.239G>A
NM_001287182.1:c.185G>A
NM_001287183.1:c.185G>A
NM_001287184.1:c.185G>A
NM_175914.4:c.194G>A
NM_178849.2:c.260G>A
NM_178850.2:c.260G>A
NM_001030003.3:c.194G>A
NM_001030004.3:c.194G>A
NM_001258355.2:c.239G>A
NM_001287182.2:c.185G>A
NM_001287184.2:c.185G>A
NM_178849.3:c.260G>A
NM_178850.3:c.260G>A
NM_000457.5:c.260G>A
NM_000457.6:c.260G>A
NM_001287183.2:c.185G>A

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Moderate PP3 PM1_Supporting

• 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 for HNF4A Version 2.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.194G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to asparagine at codon 65 (p.(Ser65Asn)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also located within the DNA binding domain (codons 37-113 of HNF4A), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.195C>A (p.(Ser65Arg)), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.194G>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 10/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting.

Met criteria codes

• 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 HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM1_Supporting: This variant is located within the DNA binding domain (codons 37-113 of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

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 contributor).
• PM5: Another missense variant, c.194G>A p.(Ser65Arg), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2024-04-06

Published on: 2024-04-06