Variant: NM_001306179.2:c.319C>A

CA386954869

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: cc023e7f-ba48-4897-be35-7dde62a32b0b

HGVS expressions

NM_001306179.2:c.319C>A
NC_000012.12:g.120979087C>A
CM000674.2:g.120979087C>A
NC_000012.11:g.121416890C>A
CM000674.1:g.121416890C>A
NC_000012.10:g.119901273C>A
NG_011731.2:g.5342C>A
ENST00000257555.11:c.319C>A
ENST00000257555.10:c.319C>A
ENST00000400024.6:c.319C>A
ENST00000402929.5:n.454C>A
ENST00000535955.5:n.42+395C>A
ENST00000538626.2:n.190+247C>A
ENST00000538646.5:c.319C>A
ENST00000540108.1:c.319C>A
ENST00000541395.5:c.319C>A
ENST00000541924.5:c.319C>A
ENST00000543427.5:c.319C>A
ENST00000544413.2:c.319C>A
ENST00000544574.5:c.72+247C>A
ENST00000560968.5:n.462C>A
ENST00000615446.4:c.-258+376C>A
ENST00000617366.4:c.319C>A
NM_000545.5:c.319C>A
NM_000545.6:c.319C>A
NM_001306179.1:c.319C>A
NM_000545.8:c.319C>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS3_Supporting PM1_Supporting PP1_Strong PP3

• Not Met criteria codes: PP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.319C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to isoleucine at codon 107 (p.(Leu107Ile)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.7509, which is greater than the MDEP threshold of 0.70 (PP3). Functional studies have also demonstrated the p.Leu107Ile protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PMID:12488960). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), however it segregated with diabetes with eight informative meioses in one family with MODY (PP1_Strong; PMID:10447526). However, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 10447526). Taken together, this evidence supports the classification of c.319C>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PP1_Strong, PP3, PM1_Supporting, PM2_Supporting, PS3_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: Functional studies demonstrated the p.Leu107Ile protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PMID:12488960) .
• PM1_Supporting: This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PP1_Strong: This variant segregated with diabetes, with eight informative meioses in one family with MODY (PP1_Strong; PMID:10447526)
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.7509, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PP4: This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 10447526).

Approved on: 2021-08-19

Published on: 2021-10-29