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]

Variant: NM_000545.6(HNF1A):c.92G>A (p.Gly31Asp)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA124487

14948 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 90aedfd1-3bfc-4e66-9183-7fa83800e4df

Approved on: 2021-12-15

Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.92G>A

NM_000545.6(HNF1A):c.92G>A (p.Gly31Asp)

NC_000012.12:g.120978860G>A

CM000674.2:g.120978860G>A

NC_000012.11:g.121416663G>A

CM000674.1:g.121416663G>A

NC_000012.10:g.119901046G>A

NG_011731.2:g.5115G>A

ENST00000257555.11:c.92G>A

ENST00000257555.10:c.92G>A

ENST00000400024.6:c.92G>A

ENST00000402929.5:n.227G>A

ENST00000535955.5:n.42+168G>A

ENST00000538626.2:n.190+20G>A

ENST00000538646.5:c.92G>A

ENST00000540108.1:c.92G>A

ENST00000541395.5:c.92G>A

ENST00000541924.5:c.92G>A

ENST00000543427.5:c.92G>A

ENST00000544413.2:c.92G>A

ENST00000544574.5:c.72+20G>A

ENST00000560968.5:n.235G>A

ENST00000615446.4:c.-258+149G>A

ENST00000617366.4:c.92G>A

NM_000545.5:c.92G>A

NM_001306179.1:c.92G>A

NM_000545.8:c.92G>A

NM_001306179.2:c.92G>A

NM_000545.8(HNF1A):c.92G>A (p.Gly31Asp)

Benign

BA1 PM1_Supporting BS3_Supporting

PS4 PP4 PP3

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.92G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 31 (p.(Gly31Asp)) 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). While it has been noted to be a pathogenic variant in the literature, there are numerous pieces of evidence that refute this classification. Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function. The variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (0.0772%), which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). It has been was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others). In summary, c.92G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): BA1, BS3_Supporting, PM1_Supporting.

BA1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000772 (.0772% or 1:1295), which is greater than or equal to the MDEP threshold for BA1 (≥0.0001) (BA1).

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).

BS3_Supporting

Functional studies demonstrated the p.Gly31Asp protein has DNA binding above 75% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting)

PS4

This variant was identified in >30 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID: 31365591, 31638168, 19169489, 26431509, 28395978, 20950394, 26059258, 19929997, 22432108, 27899486, 23551881, 24041679, 16917892, 21696527, and others).

PP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

This variant has a REVEL score of 0.591, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function

Curation History

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