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.368T>C

CA386959158

1327615 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3edaae5c-78ec-4612-a0ce-524b2b3dff39

HGVS expressions

NM_001306179.2:c.368T>C

NC_000012.12:g.120988874T>C

CM000674.2:g.120988874T>C

NC_000012.11:g.121426677T>C

CM000674.1:g.121426677T>C

NC_000012.10:g.119911060T>C

NG_011731.2:g.15129T>C

ENST00000257555.11:c.368T>C

ENST00000257555.10:c.368T>C

ENST00000400024.6:c.368T>C

ENST00000402929.5:n.503T>C

ENST00000535955.5:n.43-8617T>C

ENST00000538626.2:n.191-8617T>C

ENST00000538646.5:c.368T>C

ENST00000540108.1:c.327-4646T>C

ENST00000541395.5:c.368T>C

ENST00000541924.5:c.368T>C

ENST00000543427.5:c.368T>C

ENST00000544413.2:c.368T>C

ENST00000544574.5:c.73-7743T>C

ENST00000560968.5:n.511T>C

ENST00000615446.4:c.-257-7388T>C

ENST00000617366.4:c.368T>C

NM_000545.5:c.368T>C

NM_000545.6:c.368T>C

NM_001306179.1:c.368T>C

NM_000545.8:c.368T>C

NM_000545.8(HNF1A):c.368T>C (p.Leu123Pro)

Uncertain Significance

PM1_Supporting PP3 PM2_Supporting

PS4 PP1 PP4 PM5

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.368T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 123 (p.(Leu123Pro)) 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). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two 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 (PMID 18433912, internal lab contributor). These two individuals have a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 18433912, internal lab contributor). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 18433912). Additionally, another missense variant, c.368T>G (p.Leu123Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.368T>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 1.1, approved 6/4/2021): PP3, PM1_Supporting, 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).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

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

PS4

This variant was identified in two 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 (PMID 18433912, internal lab contributor).

PP1

This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID: 18433912).

PP4

This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 18433912, internal lab contributor).

PM5

Another missense variant, c.368T>G (p.Leu123Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2021-12-09

Published on: 2022-07-11

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