Variant: NM_000545.6(HNF1A):c.392G>A (p.Arg131Gln)

CA6831746

562373 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 650e4d16-b761-4c10-ac4d-479b2c98013e

HGVS expressions

NM_000545.6:c.392G>A
NM_000545.6(HNF1A):c.392G>A
NM_000545.6(HNF1A):c.392G>A (p.Arg131Gln)
NC_000012.12:g.120988898G>A
CM000674.2:g.120988898G>A
NC_000012.11:g.121426701G>A
CM000674.1:g.121426701G>A
NC_000012.10:g.119911084G>A
NG_011731.2:g.15153G>A
ENST00000257555.11:c.392G>A
ENST00000257555.10:c.392G>A
ENST00000400024.6:c.392G>A
ENST00000402929.5:n.527G>A
ENST00000535955.5:n.43-8593G>A
ENST00000538626.2:n.191-8593G>A
ENST00000538646.5:c.392G>A
ENST00000540108.1:c.327-4622G>A
ENST00000541395.5:c.392G>A
ENST00000541924.5:c.392G>A
ENST00000543427.5:c.392G>A
ENST00000544413.2:c.392G>A
ENST00000544574.5:c.73-7719G>A
ENST00000560968.5:n.535G>A
ENST00000615446.4:c.-257-7364G>A
ENST00000617366.4:c.392G>A
NM_000545.5:c.392G>A
NM_001306179.1:c.392G>A
NM_000545.8:c.392G>A
NM_001306179.2:c.392G>A
NM_000545.8(HNF1A):c.392G>A (p.Arg131Gln)

Pathogenic

• Met criteria codes: PS3_Supporting PM2_Supporting PP4_Moderate PP1_Strong PS2 PS4 PP3 PM1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID: 32910913 and PMID: 10585442) (PS3_Supporting). 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). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting.

Met criteria codes

• PS3_Supporting: Functional studies demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 32910913 and PMID: 10585442) (PS3_Supporting).
• PM2_Supporting: This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting).
• PP4_Moderate: This variant was identified in at least 2 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors).
• PP1_Strong: This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors).
• PS2: This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243)
• PS4: This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3).
• PM1: his 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).

Approved on: 2021-08-11

Published on: 2021-10-29