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

CA160013

134509 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2022-04-20

Published on: 2022-04-20

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]"

• Not Met criteria codes: PP3 PP4 PM1 PM2 BS1 BP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

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.

Not Met criteria codes

• 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).
• 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).
• 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.
• 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.
• 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.