Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.2:c.429C>G

CA386959959

1327604 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 485db092-d435-4791-9208-39090d7aba53

HGVS expressions

NM_001306179.2:c.429C>G

NC_000012.12:g.120988935C>G

CM000674.2:g.120988935C>G

NC_000012.11:g.121426738C>G

CM000674.1:g.121426738C>G

NC_000012.10:g.119911121C>G

NG_011731.2:g.15190C>G

ENST00000257555.11:c.429C>G

ENST00000257555.10:c.429C>G

ENST00000400024.6:c.429C>G

ENST00000402929.5:n.564C>G

ENST00000535955.5:n.43-8556C>G

ENST00000538626.2:n.191-8556C>G

ENST00000538646.5:c.429C>G

ENST00000540108.1:c.327-4585C>G

ENST00000541395.5:c.429C>G

ENST00000541924.5:c.429C>G

ENST00000543427.5:c.429C>G

ENST00000544413.2:c.429C>G

ENST00000544574.5:c.73-7682C>G

ENST00000560968.5:n.572C>G

ENST00000615446.4:c.-257-7327C>G

ENST00000617366.4:c.429C>G

NM_000545.5:c.429C>G

NM_000545.6:c.429C>G

NM_001306179.1:c.429C>G

NM_000545.8:c.429C>G

NM_000545.8(HNF1A):c.429C>G (p.His143Gln)

Likely Pathogenic

PM1 PM2_Supporting PM5_Supporting PP4 PP3

PS4 PP1

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.429C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to glutamine at codon 143 (p.(His143Gln)) 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 absent in gnomAD 2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than [or equal to] the MDEP threshold of 0.70 (PP3). Another missense variant, c.427C>T (p.His143Tyr), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.His143Gln (PM5_Supporting). 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) (PP4; internal lab contributor); however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 23348805/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 this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: PM1, PP3, PP4, PM2_Supporting, PM5_Supporting.

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 in gnomAD v2.1.1 (PM2_Supporting).

PM5_Supporting

Another missense variant, c.427C>T (p.His143Tyr), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.His143Gln (PM5_Supporting).

PP4

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) (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP threshold of 0.70 (PP3).

PS4

This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 23348805/internal lab contributor).

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: 2022-04-21

Published on: 2022-04-21

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