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_001306179.2:c.736G>T

CA386965858

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0acf64cd-df23-4af5-b62e-028bbd6fd18d

HGVS expressions

NM_001306179.2:c.736G>T

NC_000012.12:g.120994186G>T

CM000674.2:g.120994186G>T

NC_000012.11:g.121431989G>T

CM000674.1:g.121431989G>T

NC_000012.10:g.119916372G>T

NG_011731.2:g.20441G>T

ENST00000257555.11:c.736G>T

ENST00000257555.10:c.736G>T

ENST00000400024.6:c.736G>T

ENST00000402929.5:n.871G>T

ENST00000535955.5:n.43-3305G>T

ENST00000538626.2:n.191-3305G>T

ENST00000538646.5:c.549G>T

ENST00000540108.1:c.*176G>T

ENST00000541395.5:c.736G>T

ENST00000541924.5:c.713+480G>T

ENST00000543427.5:c.633+560G>T

ENST00000544413.2:c.736G>T

ENST00000544574.5:c.73-2431G>T

ENST00000560968.5:n.879G>T

ENST00000615446.4:c.-257-2076G>T

ENST00000617366.4:c.586+607G>T

NM_000545.5:c.736G>T

NM_000545.6:c.736G>T

NM_001306179.1:c.736G>T

NM_000545.8:c.736G>T

Pathogenic

PP3 PP4_Moderate PM2_Supporting PP1_Strong PM1_Supporting PS4_Moderate

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.736G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 246 (p.(V246L)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.781, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). At least 3 of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes, with at least seven informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Taken together, this evidence supports the classification of c.736G>T as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_strong, PP4_moderate, PS4_moderate, PP3, PM1_supporting, PM2_supporting.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.781, which is greater than the MDEP threshold of 0.70 (PP3).

PP4_Moderate

This variant was identified in at least 3 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; internal lab contributors).

PM2_Supporting

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

PP1_Strong

This variant segregated with diabetes, with at least seven informative meioses in four families with MODY (PP1_Strong; internal lab contributors).

PM1_Supporting

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

PS4_Moderate

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

Approved on: 2021-08-18

Published on: 2021-10-29

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