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]

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Variant: NM_000545.6(HNF1A):c.956-1G>C

CA386967823

617646 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5311cc2c-e4c3-471a-a3bb-5904395de32a

Approved on: 2021-08-24

Published on: 2021-10-29

HGVS expressions

NM_000545.6:c.956-1G>C

NM_000545.6(HNF1A):c.956-1G>C

NC_000012.12:g.120996261G>C

CM000674.2:g.120996261G>C

NC_000012.11:g.121434064G>C

CM000674.1:g.121434064G>C

NC_000012.10:g.119918447G>C

NG_011731.2:g.22516G>C

ENST00000257555.11:c.956-1G>C

ENST00000257555.10:c.956-1G>C

ENST00000400024.6:c.956-1G>C

ENST00000402929.5:n.1091-1G>C

ENST00000535955.5:n.43-1230G>C

ENST00000538626.2:n.191-1230G>C

ENST00000538646.5:c.769-1G>C

ENST00000540108.1:c.*396-1G>C

ENST00000541395.5:c.956-1G>C

ENST00000541924.5:c.714-1G>C

ENST00000543427.5:c.634-343G>C

ENST00000544413.2:c.956-1G>C

ENST00000544574.5:c.73-356G>C

ENST00000560968.5:n.894-122G>C

ENST00000615446.4:c.-257-1G>C

ENST00000617366.4:c.587-1373G>C

NM_000545.5:c.956-1G>C

NM_001306179.1:c.956-1G>C

NM_000545.8:c.956-1G>C

NM_001306179.2:c.956-1G>C

NM_000545.8(HNF1A):c.956-1G>C

Pathogenic

PS4 PP4_Moderate PM2_Supporting PVS1

PS1

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.956-1G>C variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). The nucleotide changes c.956-1G>T and c.956-1G>A, which are predicted to disrupt the intron 5 splice acceptor site to a similar extent as c.956-1G>C, have been reported in a patient with diabetes; however, these variants have not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP without the use of PS1. This variant is also absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 31658956, ClinVar ID 617646, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, sulfonylurea sensitive, and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21: PVS1, PS4, PP4_moderate, PM2_Supporting.

PS4

This variant was identified in 7 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 31658956, ClinVar ID 617646, internal lab contributors).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, sulfonylurea sensitive, and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributor).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 5 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805)

PS1

The nucleotide changes c.956-1G>T and c.956-1G>A, which are predicted to disrupt the intron 5 splice acceptor site to a similar extent as c.956-1G>C, have been reported in a patient with diabetes; however, the c.956-1G>T and c.956-1G>A variants have not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP without the use of PS1.

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