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.410C>G

CA386959674

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d7acecc3-4f87-4521-949b-5b05c1512a32

HGVS expressions

NM_001306179.2:c.410C>G

NC_000012.12:g.120988916C>G

CM000674.2:g.120988916C>G

NC_000012.11:g.121426719C>G

CM000674.1:g.121426719C>G

NC_000012.10:g.119911102C>G

NG_011731.2:g.15171C>G

ENST00000257555.11:c.410C>G

ENST00000257555.10:c.410C>G

ENST00000400024.6:c.410C>G

ENST00000402929.5:n.545C>G

ENST00000535955.5:n.43-8575C>G

ENST00000538626.2:n.191-8575C>G

ENST00000538646.5:c.410C>G

ENST00000540108.1:c.327-4604C>G

ENST00000541395.5:c.410C>G

ENST00000541924.5:c.410C>G

ENST00000543427.5:c.410C>G

ENST00000544413.2:c.410C>G

ENST00000544574.5:c.73-7701C>G

ENST00000560968.5:n.553C>G

ENST00000615446.4:c.-257-7346C>G

ENST00000617366.4:c.410C>G

NM_000545.5:c.410C>G

NM_000545.6:c.410C>G

NM_001306179.1:c.410C>G

NM_000545.8:c.410C>G

Uncertain Significance

PM1_Supporting PP4 PP3 PM2_Supporting

PS4

Evidence Links 1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.410C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to serine at codon 137 (p.(Thr137Ser)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757, internal lab contributors). However, one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). Taken together, this variant meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PP3, PP4, PM1_Supporting, PM2_Supporting).

PM1_Supporting

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

This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). PubMed:18003757

PP4

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP 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 who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757, internal lab contributors).

Approved on: 2021-08-24

Published on: 2021-10-29

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