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>G

CA386965770

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 008bf1cc-6bd3-4b37-b73c-b2e339d3b595

HGVS expressions

NM_001306179.2:c.721T>G

NC_000012.12:g.120994171T>G

CM000674.2:g.120994171T>G

NC_000012.11:g.121431974T>G

CM000674.1:g.121431974T>G

NC_000012.10:g.119916357T>G

NG_011731.2:g.20426T>G

ENST00000257555.11:c.721T>G

ENST00000257555.10:c.721T>G

ENST00000400024.6:c.721T>G

ENST00000402929.5:n.856T>G

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

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

ENST00000538646.5:c.534T>G

ENST00000540108.1:c.*161T>G

ENST00000541395.5:c.721T>G

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

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

ENST00000544413.2:c.721T>G

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

ENST00000560968.5:n.864T>G

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

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

NM_000545.5:c.721T>G

NM_000545.6:c.721T>G

NM_001306179.1:c.721T>G

NM_000545.8:c.721T>G

Likely Pathogenic

PM1_Supporting PM2_Supporting PP3 PP1_Strong

PS4 PP4

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>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to glycine at codon 241 (p.(Cys241Gly)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with disease with 12 informative meioses in three families with MODY (PP1_Strong; PMID: 9032114, PMID: 9867222). 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 (PMID: 9032114, 9867222). This variant was identified in individuals with diabetes; however, the calculated MODY probability is <50% and HNF4A was not tested (PMID: 9032114, 9867222). In summary, c.721T>G 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 6/4/2021): PM2_Supporting, PP3, PM1_Supporting, PP1_Strong.

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).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP1_Strong

This variant segregated with diabetes, with 12 informative meioses in three families with MODY (PP1_Strong; PMID: 9032114, PMID: 9867222).

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 (PMID: 9032114, 9867222).

PP4

This variant was identified in individuals with diabetes; however, the calculated MODY probability is <50% and HNF4A was not tested (PMID: 9032114, 9867222).

Approved on: 2021-11-19

Published on: 2021-11-19

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