Evidence Repository - GenboreeKB

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

Variant: NM_001306179.2:c.58G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA386952573

1327599 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7d6401b1-eb48-47e6-bb85-5d49afa7a19f

Approved on: 2021-08-18

Published on: 2021-10-29

HGVS expressions

NM_001306179.2:c.58G>C

NC_000012.12:g.120978826G>C

CM000674.2:g.120978826G>C

NC_000012.11:g.121416629G>C

CM000674.1:g.121416629G>C

NC_000012.10:g.119901012G>C

NG_011731.2:g.5081G>C

ENST00000257555.11:c.58G>C

ENST00000257555.10:c.58G>C

ENST00000400024.6:c.58G>C

ENST00000402929.5:n.193G>C

ENST00000535955.5:n.42+134G>C

ENST00000538626.2:n.176G>C

ENST00000538646.5:c.58G>C

ENST00000540108.1:c.58G>C

ENST00000541395.5:c.58G>C

ENST00000541924.5:c.58G>C

ENST00000543427.5:c.58G>C

ENST00000544413.2:c.58G>C

ENST00000544574.5:c.58G>C

ENST00000560968.5:n.201G>C

ENST00000615446.4:c.-258+115G>C

ENST00000617366.4:c.58G>C

NM_000545.5:c.58G>C

NM_000545.6:c.58G>C

NM_001306179.1:c.58G>C

NM_000545.8:c.58G>C

NM_000545.8(HNF1A):c.58G>C (p.Gly20Arg)

Likely Pathogenic

PM1_Supporting PS1 PP3 PM2_Supporting

PS4 PM5

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.58G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to arginine at codon 20 (p.(G20R)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in two unrelated individuals 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 (internal lab contributors). The nucleotide change c.58G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). Two other missense variants, c.59G>A (p.Gly20Glu) and c.59G>C (p.Gly20Ala) do not meet the criteria for likely pathogenic or pathogenic without the supporting evidence of PM5; therefore, PM5 will not be applied. Taken together, the evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PS1, PP3, PM1_Supporting, PM2_Supporting.

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).

PS1

The nucleotide change c.58G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP threshold of 0.70 (PP3).

PM2_Supporting

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

PS4

This variant was identified in two unrelated individuals 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 (internal lab contributors).

PM5

Two other missense variants, c.59G>A (p.Gly20Glu) and c.59G>C (p.Gly20Ala) do not meet the criteria for likely pathogenic or pathogenic without the supporting evidence of PM5; therefore, PM5 will not be applied.

Curation History

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