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.833G>A

CA6831838

1342955 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a742ae0a-415d-4861-950d-25954828d718

HGVS expressions

NM_001306179.2:c.833G>A

NC_000012.12:g.120994283G>A

CM000674.2:g.120994283G>A

NC_000012.11:g.121432086G>A

CM000674.1:g.121432086G>A

NC_000012.10:g.119916469G>A

NG_011731.2:g.20538G>A

ENST00000257555.11:c.833G>A

ENST00000257555.10:c.833G>A

ENST00000400024.6:c.833G>A

ENST00000402929.5:n.968G>A

ENST00000535955.5:n.43-3208G>A

ENST00000538626.2:n.191-3208G>A

ENST00000538646.5:c.646G>A

ENST00000540108.1:c.*273G>A

ENST00000541395.5:c.833G>A

ENST00000541924.5:c.713+577G>A

ENST00000543427.5:c.633+657G>A

ENST00000544413.2:c.833G>A

ENST00000544574.5:c.73-2334G>A

ENST00000560968.5:n.893+83G>A

ENST00000615446.4:c.-257-1979G>A

ENST00000617366.4:c.586+704G>A

NM_000545.5:c.833G>A

NM_000545.6:c.833G>A

NM_001306179.1:c.833G>A

NM_000545.8:c.833G>A

NM_000545.8(HNF1A):c.833G>A (p.Arg278Gln)

Uncertain Significance

PM1_Supporting PP4 PP3

BS1 PS4 PM2

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.833G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 278 (p.(Arg278Gln)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.7839, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The frequency of the c.833G>A variant in gnomAD v2.1.1 is 0.00001905, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in at least 9 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:20950394, PMID:33115208, internal lab contributors). However, at least 3 individuals with a clinical history highly specific for HNF1A-MODY were identified (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, the c.833G>A variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PP4, PM1_Supporting).

PM1_Supporting

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

PP4

This variant was identified in at least 3 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors)

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.7839, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3).

BS1

The frequency of the c.833G>A variant in gnomAD v2.1.1 is 0.00001905, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

PS4

This variant was identified in at least 9 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID:20950394, PMID:33115208, internal lab contributors).

PM2

The frequency of the c.833G>A variant in gnomAD v2.1.1 is 0.00001905, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

Approved on: 2022-02-08

Published on: 2022-07-11

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