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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000545.8(HNF1A):c.343G>T (p.Val115Leu)

CA386958889

972751 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 31709796-baaf-4493-b406-ebb77bd38325

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_000545.8:c.343G>T

NM_000545.8(HNF1A):c.343G>T (p.Val115Leu)

NC_000012.12:g.120988849G>T

CM000674.2:g.120988849G>T

NC_000012.11:g.121426652G>T

CM000674.1:g.121426652G>T

NC_000012.10:g.119911035G>T

NG_011731.2:g.15104G>T

ENST00000560968.6:c.343G>T

ENST00000257555.11:c.343G>T

ENST00000257555.10:c.343G>T

ENST00000400024.6:c.343G>T

ENST00000402929.5:n.478G>T

ENST00000535955.5:n.43-8642G>T

ENST00000538626.2:n.191-8642G>T

ENST00000538646.5:c.343G>T

ENST00000540108.1:c.327-4671G>T

ENST00000541395.5:c.343G>T

ENST00000541924.5:c.343G>T

ENST00000543427.5:c.343G>T

ENST00000544413.2:c.343G>T

ENST00000544574.5:c.73-7768G>T

ENST00000560968.5:c.486G>T

ENST00000615446.4:c.-257-7413G>T

ENST00000617366.4:c.343G>T

NM_000545.5:c.343G>T

NM_000545.6:c.343G>T

NM_001306179.1:c.343G>T

NM_001306179.2:c.343G>T

Likely Pathogenic

PM1_Supporting PP4 PP3 PS4_Moderate PM2_Supporting

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 HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.343G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 115 (p.(Val115Leu)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). In summary, c.343G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM1_Supporting, PS4_Moderate, PP3, PP4, PM2_Supporting.

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PP4

This variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.902, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PS4_Moderate

This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; ClinVar, internal lab contributors).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

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