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_001306179.2:c.956-1G>T

CA386967824

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3fe4e5e0-a6c4-4909-8a98-be6d36b53ec2

Approved on: 2021-08-24

Published on: 2021-10-29

HGVS expressions

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

NC_000012.12:g.120996261G>T

CM000674.2:g.120996261G>T

NC_000012.11:g.121434064G>T

CM000674.1:g.121434064G>T

NC_000012.10:g.119918447G>T

NG_011731.2:g.22516G>T

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pathogenic

PS1_Supporting PVS1 PM2_Supporting

PS4 PP1 PP4

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>T 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 c.956-1G>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.956-1G>T has a similar or greater predicted impact by Splice AI (0.95 and 1.0) (PS1_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual 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 (PMID 19150152). This individual had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 19150152). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID 19150152). ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting, PS1_Supporting.

PS1_Supporting

The c.956-1G>C variant at the same canonical nucleotide has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.956-1G>T has a similar or greater predicted impact by Splice AI (0.95 and 1.0) (PS1_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)

PM2_Supporting

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

PS4

This variant was identified in one individual 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 (PMID 19150152).

PP1

This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, PMID 19150152).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID 19150152).

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