Variant: NM_001306179.2:c.59G>C

CA386952583

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 2120888b-86b4-49e2-a7cc-5a05d379faba

HGVS expressions

NM_001306179.2:c.59G>C
NC_000012.12:g.120978827G>C
CM000674.2:g.120978827G>C
NC_000012.11:g.121416630G>C
CM000674.1:g.121416630G>C
NC_000012.10:g.119901013G>C
NG_011731.2:g.5082G>C
ENST00000257555.11:c.59G>C
ENST00000257555.10:c.59G>C
ENST00000400024.6:c.59G>C
ENST00000402929.5:n.194G>C
ENST00000535955.5:n.42+135G>C
ENST00000538626.2:n.177G>C
ENST00000538646.5:c.59G>C
ENST00000540108.1:c.59G>C
ENST00000541395.5:c.59G>C
ENST00000541924.5:c.59G>C
ENST00000543427.5:c.59G>C
ENST00000544413.2:c.59G>C
ENST00000544574.5:c.59G>C
ENST00000560968.5:n.202G>C
ENST00000615446.4:c.-258+116G>C
ENST00000617366.4:c.59G>C
NM_000545.5:c.59G>C
NM_000545.6:c.59G>C
NM_001306179.1:c.59G>C
NM_000545.8:c.59G>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PM1_Supporting PM5_Supporting PP3

• Not Met criteria codes: PP1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.59G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to alanine at codon 20 (p.(G20A)) of NM_000545.8. This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Ala (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). Taken together, this evidence supports the classification of the c.59G>C variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PP4_moderate, PP3, PM1_supporting, PM2_supporting, PM5_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in 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, and sulfonylurea) (PP4_Moderate; internal lab contributor).
• PM1_Supporting: This variant is located within the dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PM5_Supporting: Another missense variant, c.58G>A (p.Gly20Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Gly20Ala (PM5_Supporting).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PP1: This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor).

Approved on: 2021-08-18

Published on: 2021-10-29