Variant: NM_175914.5:c.331G>T

CA409105413

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: e844c50f-a479-4361-99cf-32cb70bc2444

Approved on: 2024-04-06

Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.331G>T
NC_000020.11:g.44413705G>T
CM000682.2:g.44413705G>T
NC_000020.10:g.43042345G>T
CM000682.1:g.43042345G>T
NC_000020.9:g.42475759G>T
NG_009818.1:g.62905G>T
ENST00000316673.9:c.331G>T
ENST00000316099.10:c.397G>T
ENST00000619550.5:c.371G>T
ENST00000683148.1:n.373G>T
ENST00000683657.1:n.1521G>T
ENST00000316099.9:c.397G>T
ENST00000316099.8:c.397G>T
ENST00000316673.8:c.331G>T
ENST00000372920.1:c.*164G>T
ENST00000415691.2:c.397G>T
ENST00000443598.6:c.397G>T
ENST00000457232.5:c.331G>T
ENST00000609795.5:c.331G>T
ENST00000619550.4:c.322G>T
NM_000457.4:c.397G>T
NM_001030003.2:c.331G>T
NM_001030004.2:c.331G>T
NM_001258355.1:c.376G>T
NM_001287182.1:c.322G>T
NM_001287183.1:c.322G>T
NM_001287184.1:c.322G>T
NM_175914.4:c.331G>T
NM_178849.2:c.397G>T
NM_178850.2:c.397G>T
NM_001030003.3:c.331G>T
NM_001030004.3:c.331G>T
NM_001258355.2:c.376G>T
NM_001287182.2:c.322G>T
NM_001287184.2:c.322G>T
NM_178849.3:c.397G>T
NM_178850.3:c.397G>T
NM_000457.5:c.397G>T
NM_000457.6:c.397G>T
NM_001287183.2:c.322G>T

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP4

• 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 for HNF4A Version 2.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.331G>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 111 (p.(Glu111Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in two 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 (internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes with two informative meioses in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.331G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/23): PVS1, PP4, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805).
• PP4: 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) (PP4; internal lab contributor).

Not Met criteria codes

• PS4: This variant was identified in two 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 (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 (PMID: 27236918, internal lab contributor).