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_001306179.1:c.733G>A

CA386965841

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f49c5251-d32e-41e2-a4d1-34a11cab80e9

HGVS expressions

NM_001306179.1:c.733G>A

NC_000012.12:g.120994183G>A

CM000674.2:g.120994183G>A

NC_000012.11:g.121431986G>A

CM000674.1:g.121431986G>A

NC_000012.10:g.119916369G>A

NG_011731.2:g.20438G>A

ENST00000257555.11:c.733G>A

ENST00000257555.10:c.733G>A

ENST00000400024.6:c.733G>A

ENST00000402929.5:n.868G>A

ENST00000535955.5:n.43-3308G>A

ENST00000538626.2:n.191-3308G>A

ENST00000538646.5:c.546G>A

ENST00000540108.1:c.*173G>A

ENST00000541395.5:c.733G>A

ENST00000541924.5:c.713+477G>A

ENST00000543427.5:c.633+557G>A

ENST00000544413.2:c.733G>A

ENST00000544574.5:c.73-2434G>A

ENST00000560968.5:n.876G>A

ENST00000615446.4:c.-257-2079G>A

ENST00000617366.4:c.586+604G>A

NM_000545.5:c.733G>A

NM_000545.6:c.733G>A

NM_000545.8:c.733G>A

NM_001306179.2:c.733G>A

Uncertain Significance

PM1_Supporting PM2_Supporting PP3

PS3 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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.733G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 245 (p.Gly245Arg) 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). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Gly245Arg protein has normal DNA binding but ~55% of transactivation activity and ~55% of nuclear localization compared to wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 28653443). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50% and negative antibodies); however, HNF4A was not tested, and PP4 will not be applied (PMIDs: 19336507, 28653433). Another missense variant, c.734C>T (p.Gly245Val), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.733G>A 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 9/30/2021): PM1_Supporting, PM2_Supporting, PP3.

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.

PM2_Supporting

This variant is absent from gnomAD.

PP3

This variant is predicted deleterious by multiple lines of computational evidence with a REVEL score of 0.962.

PS3

Functional studies demonstrated the p.Gly245Arg protein has normal DNA binding but ~55% of transactivation activity and ~55% of nuclear localization compared to wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 28653443).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result nearly 50% and negative antibodies); however, HNF4A was not tested (PMIDs: 19336507, 28653433).

PM5

Another missense variant, c.734C>T (p.Gly245Val), has been classified as a VUS by the ClinGen MDEP.

Approved on: 2022-04-12

Published on: 2022-07-12

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