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.763G>A

CA386965984

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9e46e8f8-87d3-4c13-be07-9cfabe90aac9

HGVS expressions

NM_001306179.2:c.763G>A

NC_000012.12:g.120994213G>A

CM000674.2:g.120994213G>A

NC_000012.11:g.121432016G>A

CM000674.1:g.121432016G>A

NC_000012.10:g.119916399G>A

NG_011731.2:g.20468G>A

ENST00000257555.11:c.763G>A

ENST00000257555.10:c.763G>A

ENST00000400024.6:c.763G>A

ENST00000402929.5:n.898G>A

ENST00000535955.5:n.43-3278G>A

ENST00000538626.2:n.191-3278G>A

ENST00000538646.5:c.576G>A

ENST00000540108.1:c.*203G>A

ENST00000541395.5:c.763G>A

ENST00000541924.5:c.713+507G>A

ENST00000543427.5:c.633+587G>A

ENST00000544413.2:c.763G>A

ENST00000544574.5:c.73-2404G>A

ENST00000560968.5:n.893+13G>A

ENST00000615446.4:c.-257-2049G>A

ENST00000617366.4:c.586+634G>A

NM_000545.5:c.763G>A

NM_000545.6:c.763G>A

NM_001306179.1:c.763G>A

NM_000545.8:c.763G>A

Uncertain Significance

PP3 PM2_Supporting BS3_Supporting PM1_Supporting

PS4 PP1 PP4

Evidence Links 1

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.763G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 255 (p.(Gly255Ser)) 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. 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 0.951, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in one individual with diabetes; however this number does not meet the MDEP cutoff for PS4_Supporting. The clinical history of this individual is suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 cannot be applied (internal lab contributor). This variant segregated with diabetes with one informative meiosis in this family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Functional studies demonstrated the p.Gly255Ser protein has DNA binding above 75% of wild type (PMID: 27229139; BS3_Supporting). In summary, c.763G>A meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 8/19/21): PM2_Supporting, PM1_Supporting, PP3, BS3_Supporting.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.951, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

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

BS3_Supporting

Functional studies demonstrated the p.Gly255Ser protein has DNA binding above 75% of wild type (PMID: 27229139).

Functional studies demonstrated the p.255 protein has DNA binding above 75% of wild type (PMID: 27229139). PubMed:27229139

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.

PS4

1 proband reported

PP1

1 meiosis in 1 family

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor).

Approved on: 2022-04-13

Published on: 2022-07-12

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