Variant: NM_000545.8(HNF1A):c.503G>A (p.Arg168His)

CA6831762

972756 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 2dcdfc66-1f2c-457e-a62f-5358605c3c5d

Approved on: 2024-10-24

Published on: 2024-10-24

HGVS expressions

NM_000545.8:c.503G>A
NM_000545.8(HNF1A):c.503G>A (p.Arg168His)
NC_000012.12:g.120989009G>A
CM000674.2:g.120989009G>A
NC_000012.11:g.121426812G>A
CM000674.1:g.121426812G>A
NC_000012.10:g.119911195G>A
NG_011731.2:g.15264G>A
ENST00000560968.6:c.503G>A
ENST00000257555.11:c.503G>A
ENST00000257555.10:c.503G>A
ENST00000400024.6:c.503G>A
ENST00000402929.5:n.638G>A
ENST00000535955.5:n.43-8482G>A
ENST00000538626.2:n.191-8482G>A
ENST00000538646.5:c.503G>A
ENST00000540108.1:c.327-4511G>A
ENST00000541395.5:c.503G>A
ENST00000541924.5:c.503G>A
ENST00000543427.5:c.503G>A
ENST00000544413.2:c.503G>A
ENST00000544574.5:c.73-7608G>A
ENST00000560968.5:c.646G>A
ENST00000615446.4:c.-257-7253G>A
ENST00000617366.4:c.503G>A
NM_000545.5:c.503G>A
NM_000545.6:c.503G>A
NM_001306179.1:c.503G>A
NM_001306179.2:c.503G>A

Likely Benign

• Met criteria codes: BS2 BP5 BP2 PP3 PM1_Supporting PS4_Moderate

• Not Met criteria codes: BS1 PM5 PM2

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.503G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 168 (p.(Arg168His)) 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Grpmax filtering allele frequency of the c.503G>A variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in a total of eight unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors). However, in one case this variant was detected in trans with another variant in HNF1A that is classified as likely pathogenic by the ClinGen MDEP (BP2, internal lab contributors). In another case, this variant was detected in an individual with diabetes, who also harbored a whole gene deletion of HNF1B (BP5, internal lab contributors). Therefore, that leaves six individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes and this variant (PS4_Moderate, internal lab contributors). This variant was also identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2, internal lab contributors). Another missense variant at the same codon, c.503G>C p.Arg168Pro, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.503G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS2, BP2, BP5, PS4_Moderate, PP3, PM1_Supporting.

Met criteria codes

• BS2: This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2, internal lab contributors).
• BP5: This variant was detected in an individual with diabetes, who also harbored a whole gene deletion of HNF1B (BP5, internal lab contributors).
• BP2: This variant has been observed in trans with another variant in HNF1A that is classified as likely pathogenic by the ClinGen MDEP (BP2, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• 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).
• PS4_Moderate: This variant was identified in six unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors).

Not Met criteria codes

• BS1: The Grpmax filtering allele frequency of the c.503G>A variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
• PM5: Another missense variant, c.503G>C p.Arg168Pro, has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.
• PM2: The Grpmax filtering allele frequency of the c.503G>A variant in gnomAD v2.1.1 is 0.000017, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.