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.722G>A

CA386965780

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6c94833d-b4d3-4a3a-9b0e-3d50dbe72aa8

HGVS expressions

NM_001306179.2:c.722G>A

NC_000012.12:g.120994172G>A

CM000674.2:g.120994172G>A

NC_000012.11:g.121431975G>A

CM000674.1:g.121431975G>A

NC_000012.10:g.119916358G>A

NG_011731.2:g.20427G>A

ENST00000257555.11:c.722G>A

ENST00000257555.10:c.722G>A

ENST00000400024.6:c.722G>A

ENST00000402929.5:n.857G>A

ENST00000535955.5:n.43-3319G>A

ENST00000538626.2:n.191-3319G>A

ENST00000538646.5:c.535G>A

ENST00000540108.1:c.*162G>A

ENST00000541395.5:c.722G>A

ENST00000541924.5:c.713+466G>A

ENST00000543427.5:c.633+546G>A

ENST00000544413.2:c.722G>A

ENST00000544574.5:c.73-2445G>A

ENST00000560968.5:n.865G>A

ENST00000615446.4:c.-257-2090G>A

ENST00000617366.4:c.586+593G>A

NM_000545.5:c.722G>A

NM_000545.6:c.722G>A

NM_001306179.1:c.722G>A

NM_000545.8:c.722G>A

Uncertain Significance

PM5_Supporting PM1_Supporting PM2_Supporting PP3

PS4 PP4 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.722G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of cysteine to tyrosine at codon 241 (p.(Cys241Tyr)) of NM_000545.8. This variant is located within a conserved region of the DNA binding of HNF1A, which is critical for the protein’s function (PM1_Supporting). Additionally, 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 0.963, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This individual also has a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor). Additionally, two other missense variants, c.721T>G (p.Cys241Gly) and c.721T>C (p.Cys241Arg), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.722G>A meets the criteria to be classified as variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, PP3, PM1_Supporting, PM5_Moderate.

PM5_Supporting

Two other missense variants, c.721T>G (p.Cys241Gly) and c.721T>C (p.Cys241Arg), have been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM1_Supporting

This variant is located within a conserved region of the HNF1A DNA binding domain (codons 107-174 and 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.963, which is greater than the MDEP VCEP 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 cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributor).

PP1

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

Approved on: 2021-11-19

Published on: 2021-11-19

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