Variant: NM_000545.6(HNF1A):c.392G>T (p.Arg131Leu)

CA386959454

447488 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 8cd02eb2-ab8e-4166-b993-3e7866532520

HGVS expressions

NM_000545.6:c.392G>T
NM_000545.6(HNF1A):c.392G>T (p.Arg131Leu)
NC_000012.12:g.120988898G>T
CM000674.2:g.120988898G>T
NC_000012.11:g.121426701G>T
CM000674.1:g.121426701G>T
NC_000012.10:g.119911084G>T
NG_011731.2:g.15153G>T
ENST00000257555.11:c.392G>T
ENST00000257555.10:c.392G>T
ENST00000400024.6:c.392G>T
ENST00000402929.5:n.527G>T
ENST00000535955.5:n.43-8593G>T
ENST00000538626.2:n.191-8593G>T
ENST00000538646.5:c.392G>T
ENST00000540108.1:c.327-4622G>T
ENST00000541395.5:c.392G>T
ENST00000541924.5:c.392G>T
ENST00000543427.5:c.392G>T
ENST00000544413.2:c.392G>T
ENST00000544574.5:c.73-7719G>T
ENST00000560968.5:n.535G>T
ENST00000615446.4:c.-257-7364G>T
ENST00000617366.4:c.392G>T
NM_000545.5:c.392G>T
NM_001306179.1:c.392G>T
NM_000545.8:c.392G>T
NM_001306179.2:c.392G>T
NM_000545.8(HNF1A):c.392G>T (p.Arg131Leu)

Likely Pathogenic

• Met criteria codes: PP3 PM5_Strong PM1 PM2_Supporting

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.392G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to leucine at codon 131 (p.(R131L)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.392G>A (p.Arg131Gln) and c.391C>T (p.Arg131Trp), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 447488). Taken together, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PM5_Strong, PM1, PP3, PM2_Supporting.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.994, which is greater than the MDEP threshold of 0.70 (PP3).
• PM5_Strong: Two other missense variants, c.392G>A (p.Arg131Gln) and c.391C>T (p.Arg131Trp), have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong).
• PM1: This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant was identified in an individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID: 447488).

Approved on: 2021-08-18

Published on: 2021-10-29