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.725T>C

CA386965798

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1d61d7bf-dc0f-4ef4-a8ad-7ecaee94f08c

HGVS expressions

NM_001306179.2:c.725T>C

NC_000012.12:g.120994175T>C

CM000674.2:g.120994175T>C

NC_000012.11:g.121431978T>C

CM000674.1:g.121431978T>C

NC_000012.10:g.119916361T>C

NG_011731.2:g.20430T>C

ENST00000257555.11:c.725T>C

ENST00000257555.10:c.725T>C

ENST00000400024.6:c.725T>C

ENST00000402929.5:n.860T>C

ENST00000535955.5:n.43-3316T>C

ENST00000538626.2:n.191-3316T>C

ENST00000538646.5:c.538T>C

ENST00000540108.1:c.*165T>C

ENST00000541395.5:c.725T>C

ENST00000541924.5:c.713+469T>C

ENST00000543427.5:c.633+549T>C

ENST00000544413.2:c.725T>C

ENST00000544574.5:c.73-2442T>C

ENST00000560968.5:n.868T>C

ENST00000615446.4:c.-257-2087T>C

ENST00000617366.4:c.586+596T>C

NM_000545.5:c.725T>C

NM_000545.6:c.725T>C

NM_001306179.1:c.725T>C

NM_000545.8:c.725T>C

Uncertain Significance

PM2_Supporting PM1_Supporting

PS4 PP4 PP3

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.725T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 242 (p.(Ile242Thr)) 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 (PM1_Supporting). This variant has a REVEL score of 0.624, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function. This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate, and the MODY probability is unable to be calculated due to lack of clinical information (PMID: 23771925). In summary, c.725T>C 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 6/4/21): PM2_Supporting, PM1_Supporting.

PM2_Supporting

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

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 (PM1_Supporting).

PS4

This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 23771925).

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: 23771925).

PP3

This variant has a REVEL score of 0.624, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function.

Approved on: 2021-11-19

Published on: 2021-11-19

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