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.342dup

CA2018007656

1342953 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7a934922-1452-47d1-9a71-1b320f1841c5

HGVS expressions

NM_001306179.2:c.342dup

NC_000012.12:g.120988848dup

CM000674.2:g.120988848dup

NC_000012.11:g.121426651dup

CM000674.1:g.121426651dup

NC_000012.10:g.119911034dup

NG_011731.2:g.15103dup

ENST00000257555.11:c.342dup

ENST00000257555.10:c.342dup

ENST00000400024.6:c.342dup

ENST00000402929.5:n.477dup

ENST00000535955.5:n.43-8643dup

ENST00000538626.2:n.191-8643dup

ENST00000538646.5:c.342dup

ENST00000540108.1:c.327-4672dup

ENST00000541395.5:c.342dup

ENST00000541924.5:c.342dup

ENST00000543427.5:c.342dup

ENST00000544413.2:c.342dup

ENST00000544574.5:c.73-7769dup

ENST00000560968.5:n.485dup

ENST00000615446.4:c.-257-7414dup

ENST00000617366.4:c.342dup

NM_000545.5:c.342dup

NM_000545.6:c.342dup

NM_001306179.1:c.342dup

NM_000545.8:c.342dup

NM_000545.8(HNF1A):c.342dup (p.Val115fs)

Likely Pathogenic

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

PVS1 PM2_Supporting

PS4 PP4 BA1 BS1

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.342dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 115 (NM_000545.8), adding 73 novel amino acids before encountering a stop codon (p.(Val115CysfsTer73)). This variant, located in biologically-relevant exon 2 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 absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PS4_Moderate also cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, c.342dup 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.

PVS1

This variant, located in biologically-relevant exon 2 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).

PM2_Supporting

Absent in gnomAD v2.1.1 (PM2_Supporting).

PS4

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

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (internal lab contributor).

BA1

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

BS1

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

Approved on: 2022-02-08

Published on: 2022-07-11

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