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.721T>C

CA386965775

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 905bc8c7-34b0-4626-a264-eae3dce2e2a1

HGVS expressions

NM_001306179.2:c.721T>C

NC_000012.12:g.120994171T>C

CM000674.2:g.120994171T>C

NC_000012.11:g.121431974T>C

CM000674.1:g.121431974T>C

NC_000012.10:g.119916357T>C

NG_011731.2:g.20426T>C

ENST00000257555.11:c.721T>C

ENST00000257555.10:c.721T>C

ENST00000400024.6:c.721T>C

ENST00000402929.5:n.856T>C

ENST00000535955.5:n.43-3320T>C

ENST00000538626.2:n.191-3320T>C

ENST00000538646.5:c.534T>C

ENST00000540108.1:c.*161T>C

ENST00000541395.5:c.721T>C

ENST00000541924.5:c.713+465T>C

ENST00000543427.5:c.633+545T>C

ENST00000544413.2:c.721T>C

ENST00000544574.5:c.73-2446T>C

ENST00000560968.5:n.864T>C

ENST00000615446.4:c.-257-2091T>C

ENST00000617366.4:c.586+592T>C

NM_000545.5:c.721T>C

NM_000545.6:c.721T>C

NM_001306179.1:c.721T>C

NM_000545.8:c.721T>C

Likely Pathogenic

PS4_Moderate PM1_Supporting PP4_Moderate PP1 PP3 PM5_Supporting PM2_Supporting

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.721T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to arginine at codon 241 (p.(Cys241Arg)) of NM_000545.8. This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.721T>G p.(Cys241Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant segregated with disease with 2 informative meioses in 2 families with MODY (PP1; internal lab contributor). 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, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). In summary, c.721T>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 1.1, approved 6/4/21): PM2_Supporting, PP3, PM1_Supporting, PS4_Moderate, PP1, PP4_Moderate, PM5_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).

PM1_Supporting

This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PP4_Moderate

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, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor).

PP1

This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.971, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM5_Supporting

Another missense variant, c.721T>G p.(Cys241Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM2_Supporting

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

Approved on: 2021-11-19

Published on: 2021-11-19

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