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.727C>G

CA386965806

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1a0d29ca-d4fb-4db2-9e11-138c0e0a2c0e

HGVS expressions

NM_001306179.2:c.727C>G

NC_000012.12:g.120994177C>G

CM000674.2:g.120994177C>G

NC_000012.11:g.121431980C>G

CM000674.1:g.121431980C>G

NC_000012.10:g.119916363C>G

NG_011731.2:g.20432C>G

ENST00000257555.11:c.727C>G

ENST00000257555.10:c.727C>G

ENST00000400024.6:c.727C>G

ENST00000402929.5:n.862C>G

ENST00000535955.5:n.43-3314C>G

ENST00000538626.2:n.191-3314C>G

ENST00000538646.5:c.540C>G

ENST00000540108.1:c.*167C>G

ENST00000541395.5:c.727C>G

ENST00000541924.5:c.713+471C>G

ENST00000543427.5:c.633+551C>G

ENST00000544413.2:c.727C>G

ENST00000544574.5:c.73-2440C>G

ENST00000560968.5:n.870C>G

ENST00000615446.4:c.-257-2085C>G

ENST00000617366.4:c.586+598C>G

NM_000545.5:c.727C>G

NM_000545.6:c.727C>G

NM_001306179.1:c.727C>G

NM_000545.8:c.727C>G

Uncertain Significance

PM1_Supporting PP3 PM2_Supporting

PP4 PP1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.727C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to glutamic acid at codon 243 (p.(Gln243Glu)) 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). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8659, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 15657605). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 15657605). In summary, c.727C>G 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 2.0.0, approved 1/11/2023): PP3, PM1_Supporting, PM2_Supporting.

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 (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8659, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

Absent from gnomAD v2.1.1 (PM2_Supporting).

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 15657605).

PP1

This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918; 15657605).

Approved on: 2023-07-30

Published on: 2023-07-30

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