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.732A>T

CA386965838

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1082042b-3a8d-41ef-b215-9c4b6c8b6711

HGVS expressions

NM_001306179.1:c.732A>T

NC_000012.12:g.120994182A>T

CM000674.2:g.120994182A>T

NC_000012.11:g.121431985A>T

CM000674.1:g.121431985A>T

NC_000012.10:g.119916368A>T

NG_011731.2:g.20437A>T

ENST00000257555.11:c.732A>T

ENST00000257555.10:c.732A>T

ENST00000400024.6:c.732A>T

ENST00000402929.5:n.867A>T

ENST00000535955.5:n.43-3309A>T

ENST00000538626.2:n.191-3309A>T

ENST00000538646.5:c.545A>T

ENST00000540108.1:c.*172A>T

ENST00000541395.5:c.732A>T

ENST00000541924.5:c.713+476A>T

ENST00000543427.5:c.633+556A>T

ENST00000544413.2:c.732A>T

ENST00000544574.5:c.73-2435A>T

ENST00000560968.5:n.875A>T

ENST00000615446.4:c.-257-2080A>T

ENST00000617366.4:c.586+603A>T

NM_000545.5:c.732A>T

NM_000545.6:c.732A>T

NM_000545.8:c.732A>T

NM_001306179.2:c.732A>T

Uncertain Significance

PM1_Supporting PP3 PM2_Supporting

PS4 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.732A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 244 (p.Arg244Ser) 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 0.723, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors), and PP4 cannot be applied. Another missense variant, c.731G>T (p.Arg244Ile), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 cannot be applied. In summary, c.732A>T 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.

PP3

This variant is predicted deleterious by multiple lines of computational evidence with a REVEL score of 0.723

PM2_Supporting

This variant is absent from gnomAD.

PS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributors).

PM5

Another missense variant, c.731G>T (p.Arg244Ile), has been classified as a VUS by the ClinGen MDEP.

Approved on: 2022-04-12

Published on: 2022-07-12

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