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_001306179.1:c.696dup

CA913203569

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9a09a66c-da35-4fc9-99dc-38e314cb2bb5

HGVS expressions

NM_001306179.1:c.696dup

NC_000012.12:g.120993689dup

CM000674.2:g.120993689dup

NC_000012.11:g.121431492dup

CM000674.1:g.121431492dup

NC_000012.10:g.119915875dup

NG_011731.2:g.19944dup

ENST00000257555.11:c.696dup

ENST00000257555.10:c.696dup

ENST00000400024.6:c.696dup

ENST00000402929.5:n.831dup

ENST00000535955.5:n.43-3802dup

ENST00000538626.2:n.191-3802dup

ENST00000538646.5:c.527-475dup

ENST00000540108.1:c.*136dup

ENST00000541395.5:c.696dup

ENST00000541924.5:c.696dup

ENST00000543427.5:c.633+63dup

ENST00000544413.2:c.696dup

ENST00000544574.5:c.73-2928dup

ENST00000560968.5:n.839dup

ENST00000615446.4:c.-257-2573dup

ENST00000617366.4:c.586+110dup

NM_000545.5:c.696dup

NM_000545.6:c.696dup

NM_000545.8:c.696dup

NM_001306179.2:c.696dup

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PM2_Supporting PVS1

PS4 PP4

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.696dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 233 of NM_000545.8, adding 6 novel amino acids before encountering a stop codon (p.Val233SerfsTer6). This variant, located in biologically-relevant exon 3 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PP4 cannot be applied because the MODY probability cannot be calculated due to lack of family history information, and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.696dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD.

PVS1

This variant is predicted to cause loss of function and result in the nonsense mediated decay of a biologically relevant exon.

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).

PP4

This variant was identified in two individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of family history information (internal lab contributors).

Approved on: 2022-04-12

Published on: 2022-07-12

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