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.412G>A

CA386959690

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 456fde1f-a633-4507-a10d-ac86639cd97c

HGVS expressions

NM_001306179.2:c.412G>A

NC_000012.12:g.120988918G>A

CM000674.2:g.120988918G>A

NC_000012.11:g.121426721G>A

CM000674.1:g.121426721G>A

NC_000012.10:g.119911104G>A

NG_011731.2:g.15173G>A

ENST00000257555.11:c.412G>A

ENST00000257555.10:c.412G>A

ENST00000400024.6:c.412G>A

ENST00000402929.5:n.547G>A

ENST00000535955.5:n.43-8573G>A

ENST00000538626.2:n.191-8573G>A

ENST00000538646.5:c.412G>A

ENST00000540108.1:c.327-4602G>A

ENST00000541395.5:c.412G>A

ENST00000541924.5:c.412G>A

ENST00000543427.5:c.412G>A

ENST00000544413.2:c.412G>A

ENST00000544574.5:c.73-7699G>A

ENST00000560968.5:n.555G>A

ENST00000615446.4:c.-257-7344G>A

ENST00000617366.4:c.412G>A

NM_000545.5:c.412G>A

NM_000545.6:c.412G>A

NM_001306179.1:c.412G>A

NM_000545.8:c.412G>A

Uncertain Significance

PM1_Supporting PM2_Supporting PP3

PS4 PP4

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.412G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to serine at codon 138 (p.(Gly138Ser)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9539, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in two unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757; internal lab contributors). Additionally, the calculated MODY probability in these individuals is <50% and HNF4A was not tested (internal lab contributor). In summary, this variant meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied as specified by the GlinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PP3, PM1_Supporting, PM2_Supporting.

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).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9539, which is greater than the MDEP threshold of 0.70 (PP3).

PS4

This variant was identified in two unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757; internal lab contributors).

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor).

Approved on: 2021-08-24

Published on: 2021-10-29

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