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.638T>C

CA386964662

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1d21620e-62c4-42c5-ab67-dd02dcd40182

HGVS expressions

NM_001306179.2:c.638T>C

NC_000012.12:g.120993631T>C

CM000674.2:g.120993631T>C

NC_000012.11:g.121431434T>C

CM000674.1:g.121431434T>C

NC_000012.10:g.119915817T>C

NG_011731.2:g.19886T>C

ENST00000560968.6:c.638T>C

ENST00000257555.11:c.638T>C

ENST00000257555.10:c.638T>C

ENST00000400024.6:c.638T>C

ENST00000402929.5:n.773T>C

ENST00000535955.5:n.43-3860T>C

ENST00000538626.2:n.191-3860T>C

ENST00000538646.5:c.527-533T>C

ENST00000540108.1:c.*78T>C

ENST00000541395.5:c.638T>C

ENST00000541924.5:c.638T>C

ENST00000543427.5:c.633+5T>C

ENST00000544413.2:c.638T>C

ENST00000544574.5:c.73-2986T>C

ENST00000560968.5:c.781T>C

ENST00000615446.4:c.-257-2631T>C

ENST00000617366.4:c.586+52T>C

NM_000545.5:c.638T>C

NM_000545.6:c.638T>C

NM_001306179.1:c.638T>C

NM_000545.8:c.638T>C

Uncertain Significance

PM2_Supporting PM5_Supporting PM1_Supporting PP3

PS4 PP4 PP1

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.638T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 213 (p.(Ile213Thr)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual 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 (PMID: 19169489). 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, PMID: 19169489). Additionally, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 19169489). Another missense variant, c.637A>T p.(Ile213Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.638T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting.

PM2_Supporting

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

PM5_Supporting

Another missense variant, c.637A>T p.(Ile213Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_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).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PS4

This variant was identified in an individual 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 (PMID: 19169489).

PP4

This variant was identified in an individual with diabetes and negative antibodies; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 19169489).

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, PMID: 19169489).

Approved on: 2024-06-09

Published on: 2024-06-09

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