Variant: NM_001306179.2:c.16A>T

CA386952188

1342950 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 40e56486-3c05-4f63-96ab-b44464103a89

HGVS expressions

NM_001306179.2:c.16A>T
NC_000012.12:g.120978784A>T
CM000674.2:g.120978784A>T
NC_000012.11:g.121416587A>T
CM000674.1:g.121416587A>T
NC_000012.10:g.119900970A>T
NG_011731.2:g.5039A>T
ENST00000257555.11:c.16A>T
ENST00000257555.10:c.16A>T
ENST00000400024.6:c.16A>T
ENST00000402929.5:n.151A>T
ENST00000535955.5:n.42+92A>T
ENST00000538626.2:n.134A>T
ENST00000538646.5:c.16A>T
ENST00000540108.1:c.16A>T
ENST00000541395.5:c.16A>T
ENST00000541924.5:c.16A>T
ENST00000543427.5:c.16A>T
ENST00000544413.2:c.16A>T
ENST00000544574.5:c.16A>T
ENST00000560968.5:n.159A>T
ENST00000615446.4:c.-258+73A>T
ENST00000617366.4:c.16A>T
NM_000545.5:c.16A>T
NM_000545.6:c.16A>T
NM_001306179.1:c.16A>T
NM_000545.8:c.16A>T
NM_000545.8(HNF1A):c.16A>T (p.Ser6Cys)

Likely Pathogenic

• Met criteria codes: PM5_Supporting PM2_Supporting PP4_Moderate PM1_Supporting PP3

• Not Met criteria codes: PS4 PP1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.16A>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to cysteine at codon 6 (p.(Ser6Cys)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8529, which is greater than the MDEP threshold of 0.70 (PP3). Lastly, another missense variant (p.(Ser6Asn)) has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PP4_Moderate, PM2_Supporting, PP3, PM5_Supporting.

Met criteria codes

• PM5_Supporting: Another missense variant, [(p. Ser6Asn)] has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive) (PP4_Moderate; internal lab contributor).
• PM1_Supporting: This variant is located within the DNA binding of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.8529, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-03-04

Published on: 2022-07-11