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_000545.8(HNF1A):c.557T>C (p.Ile186Thr)

CA160013

134509 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0f175643-63fc-4154-87fd-815b6a404dff

HGVS expressions

NM_000545.8:c.557T>C

NM_000545.8(HNF1A):c.557T>C (p.Ile186Thr)

NC_000012.12:g.120993550T>C

CM000674.2:g.120993550T>C

NC_000012.11:g.121431353T>C

CM000674.1:g.121431353T>C

NC_000012.10:g.119915736T>C

NG_011731.2:g.19805T>C

ENST00000257555.11:c.557T>C

ENST00000257555.10:c.557T>C

ENST00000400024.6:c.557T>C

ENST00000402929.5:n.692T>C

ENST00000535955.5:n.43-3941T>C

ENST00000538626.2:n.191-3941T>C

ENST00000538646.5:c.527-614T>C

ENST00000540108.1:c.357T>C

ENST00000541395.5:c.557T>C

ENST00000541924.5:c.557T>C

ENST00000543427.5:c.557T>C

ENST00000544413.2:c.557T>C

ENST00000544574.5:c.73-3067T>C

ENST00000560968.5:n.700T>C

ENST00000615446.4:c.-257-2712T>C

ENST00000617366.4:c.557T>C

NM_000545.5:c.557T>C

NM_000545.6:c.557T>C

NM_001306179.1:c.557T>C

NM_001306179.2:c.557T>C

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"

BP4 PP3 PP4 PM2 PM1 BS1

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.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant is located the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00005278, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (Internal lab contributors). In summary, c.557T>C 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 VCEP (specification version 1.1, approved 9/30/2021): None.

BP4

This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.

PP3

This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.

PP4

This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (Internal lab contributors).

PM2

The frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00005278, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

PM1

This variant is located the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280).

BS1

The frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00005278, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

Approved on: 2022-04-20

Published on: 2022-04-20

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