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_000545.6(HNF1A):c.872C>G (p.Pro291Arg)

CA214336

36833 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cf6afdce-91dc-447f-b339-298c57e3ec78

HGVS expressions

NM_000545.6(HNF1A):c.872C>G

NM_000545.6:c.872C>G

NM_000545.6(HNF1A):c.872C>G (p.Pro291Arg)

NC_000012.12:g.120994322C>G

CM000674.2:g.120994322C>G

NC_000012.11:g.121432125C>G

CM000674.1:g.121432125C>G

NC_000012.10:g.119916508C>G

NG_011731.2:g.20577C>G

ENST00000257555.11:c.872C>G

ENST00000257555.10:c.872C>G

ENST00000400024.6:c.872C>G

ENST00000402929.5:n.1007C>G

ENST00000535955.5:n.43-3169C>G

ENST00000538626.2:n.191-3169C>G

ENST00000538646.5:c.685C>G

ENST00000540108.1:c.*312C>G

ENST00000541395.5:c.872C>G

ENST00000541924.5:c.713+616C>G

ENST00000543427.5:c.633+696C>G

ENST00000544413.2:c.872C>G

ENST00000544574.5:c.73-2295C>G

ENST00000560968.5:n.893+122C>G

ENST00000615446.4:c.-257-1940C>G

ENST00000617366.4:c.586+743C>G

NM_000545.5:c.872C>G

NM_001306179.1:c.872C>G

NM_000545.8:c.872C>G

NM_001306179.2:c.872C>G

NM_000545.8(HNF1A):c.872C>G (p.Pro291Arg)

Uncertain Significance

BS1

PS4 PP3 PM2 PM5 BS2

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.872C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 291 (p.(Pro291Arg)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009402, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). 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). Two other missense variants, c. 871C>A, p. Pro291Thr and c.871C>G, p.Pro291Ala, have been classified as VUS; therefore, PM5 will not be applied. Lastly, this variant has a REVEL score of 0.4189, which is between the ClinGen MDEP thresholds for PP3 and BP4, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.872C>G meets the criteria to be classified as 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): BS1.

BS1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009402, which is greater than or equal to the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1).

PS4

Two cases in large US biobank

PP3

This variant has a REVEL score of 0.4189, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function

PM2

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

PM5

No other variants at Pro291 are curated as pathogenic or likely pathogenic

BS2

Two non-diabetic individuals in a large US biobank, one age <70, one age unknown.

Approved on: 2022-08-05

Published on: 2022-08-05

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