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

CA6831794

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 79fce260-ca86-47ca-8eec-de8fcb84959f

HGVS expressions

NM_001306179.2:c.682G>A

NC_000012.12:g.120993675G>A

CM000674.2:g.120993675G>A

NC_000012.11:g.121431478G>A

CM000674.1:g.121431478G>A

NC_000012.10:g.119915861G>A

NG_011731.2:g.19930G>A

ENST00000257555.11:c.682G>A

ENST00000257555.10:c.682G>A

ENST00000400024.6:c.682G>A

ENST00000402929.5:n.817G>A

ENST00000535955.5:n.43-3816G>A

ENST00000538626.2:n.191-3816G>A

ENST00000538646.5:c.527-489G>A

ENST00000540108.1:c.*122G>A

ENST00000541395.5:c.682G>A

ENST00000541924.5:c.682G>A

ENST00000543427.5:c.633+49G>A

ENST00000544413.2:c.682G>A

ENST00000544574.5:c.73-2942G>A

ENST00000560968.5:n.825G>A

ENST00000615446.4:c.-257-2587G>A

ENST00000617366.4:c.586+96G>A

NM_000545.5:c.682G>A

NM_000545.6:c.682G>A

NM_001306179.1:c.682G>A

NM_000545.8:c.682G>A

Uncertain Significance

PM1_Supporting PP4 PP3 PM2_Supporting

PM5

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.682G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 228 (p.(Glu228Lys)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.8799, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant has a minor allele frequency of 0.0000088 in the gnomAD v2.1.1 European non-Finnish population and zero copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). The c.682G>A variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). Another missense variant, c.683A>G p.Glu228Gly, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.682G>A meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3, PP4.

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

PP4

This variant was identified in one 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 0.8799, which is greater than or equal to the MDEP VCEP threshold of 0.70.

PM2_Supporting

This variant has a minor allele frequency of 0.0000088 in the gnomAD v2.1.1 European non-Finnish population and zero copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation).

PM5

Another missense variant, c.683A>G p.Glu228Gly, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2022-08-05

Published on: 2022-08-05

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