Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_175914.5(HNF4A):c.2T>C (p.Met1Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409109840

689636 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f6d4c84b-afc3-4936-82c3-f4fe26b1e27e

Approved on: 2024-01-02

Published on: 2024-01-02

HGVS expressions

NM_175914.5:c.2T>C

NM_175914.5(HNF4A):c.2T>C (p.Met1Thr)

NC_000020.11:g.44355806T>C

CM000682.2:g.44355806T>C

NC_000020.10:g.42984446T>C

CM000682.1:g.42984446T>C

NC_000020.9:g.42417860T>C

NG_009818.1:g.5006T>C

ENST00000316673.8:c.2T>C

ENST00000457232.5:c.2T>C

ENST00000609262.5:c.-230T>C

ENST00000609795.5:c.2T>C

ENST00000619550.4:c.-230T>C

NM_001030003.2:c.2T>C

NM_001030004.2:c.2T>C

NM_001287182.1:c.-230T>C

NM_001287183.1:c.-230T>C

NM_001287184.1:c.-230T>C

NM_175914.4:c.2T>C

NM_001030003.3:c.2T>C

NM_001030004.3:c.2T>C

NM_001287182.2:c.-230T>C

NM_001287184.2:c.-230T>C

NM_001287183.2:c.-230T>C

Likely Pathogenic

PVS1_Strong PM2_Supporting PS4_Moderate

PP4

Evidence Links 0

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 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.2T>C variant in the hepatic nuclear factor-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population) (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.2T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PS4_Moderate, PM2_Supporting.

PVS1_Strong

By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PMID: 23348805).

PM2_Supporting

This variant is only present in one copy in the Latino/Admixed American subpopulation in gnomAD v2.1.1 and therefore a Popmax FAF is unavailable. Still, the variant meets the ClinGen MDEP threshold for PM2_Supporting (gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population). (PM2_Supporting)

PS4_Moderate

This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PP4_Moderate; internal lab contributors).

PP4

This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (SCV002301126.2; SCV001996322.2; Internal lab contributors).

Curation History

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