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_001306179.2:c.77T>C

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386952705

1676683 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c4447168-1bef-4f71-a54c-cffea44504f7

Approved on: 2022-04-02

Published on: 2022-07-12

HGVS expressions

NM_001306179.2:c.77T>C

NC_000012.12:g.120978845T>C

CM000674.2:g.120978845T>C

NC_000012.11:g.121416648T>C

CM000674.1:g.121416648T>C

NC_000012.10:g.119901031T>C

NG_011731.2:g.5100T>C

ENST00000560968.6:c.77T>C

ENST00000257555.11:c.77T>C

ENST00000257555.10:c.77T>C

ENST00000400024.6:c.77T>C

ENST00000402929.5:n.212T>C

ENST00000535955.5:n.42+153T>C

ENST00000538626.2:n.190+5T>C

ENST00000538646.5:c.77T>C

ENST00000540108.1:c.77T>C

ENST00000541395.5:c.77T>C

ENST00000541924.5:c.77T>C

ENST00000543427.5:c.77T>C

ENST00000544413.2:c.77T>C

ENST00000544574.5:c.72+5T>C

ENST00000560968.5:c.220T>C

ENST00000615446.4:c.-258+134T>C

ENST00000617366.4:c.77T>C

NM_000545.5:c.77T>C

NM_000545.6:c.77T>C

NM_001306179.1:c.77T>C

NM_000545.8:c.77T>C

Likely Pathogenic

PM2_Supporting PP1_Moderate PS2_Supporting PM1_Supporting PP3 PP4

PS4

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 Version 1.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.77T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 26 (p.(Leu26Pro)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.946, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result <50%) (PS2_Supporting; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, not tested for HNF4A, but individual had hepatocellular adenomas, highly specific for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes, with four informative meioses in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in three 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). In summary, c.77T>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 1.0, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3, PS2_Supporting, PP4, PP1_Moderate

PM2_Supporting

Absent from gnomAD 2.1.1.

PP1_Moderate

This variant segregated with diabetes, with 4 informative meioses in 1 family with MODY (internal lab contributors).

PS2_Supporting

This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result <50%) (internal lab contributors).

PM1_Supporting

In the dimerization domain.

PP3

REVEL = 0.946

PP4

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, HNF4A not tested but individual had hepatocellular adenomas, highly specific for HNF1A) (internal lab contributors).

PS4

This variant was identified in three 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).

Curation History

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