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.1501+1G>T

CA386970411

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8a6ba58f-e689-457b-8592-9848d5ca4ca4

Approved on: 2022-05-03

Published on: 2022-05-03

HGVS expressions

NM_001306179.2:c.1501+1G>T

NC_000012.12:g.120997666G>T

CM000674.2:g.120997666G>T

NC_000012.11:g.121435469G>T

CM000674.1:g.121435469G>T

NC_000012.10:g.119919852G>T

NG_011731.2:g.23921G>T

ENST00000257555.11:c.1501+1G>T

ENST00000257555.10:c.1501+1G>T

ENST00000400024.6:c.1502G>T

ENST00000402929.5:n.2368G>T

ENST00000535955.5:n.218G>T

ENST00000538626.2:n.366G>T

ENST00000538646.5:c.*478G>T

ENST00000540108.1:c.*941+1G>T

ENST00000541395.5:c.1501+1G>T

ENST00000541924.5:c.*516G>T

ENST00000543255.1:n.546G>T

ENST00000543427.5:c.964+1G>T

ENST00000544413.2:c.1501+1G>T

ENST00000544574.5:c.*265G>T

ENST00000560968.5:n.1318+1G>T

ENST00000615446.4:c.289+1G>T

ENST00000617366.4:c.618+1G>T

NM_000545.5:c.1501+1G>T

NM_000545.6:c.1501+1G>T

NM_001306179.1:c.1501+1G>T

NM_000545.8:c.1501+1G>T

Likely Pathogenic

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

PVS1 PM2_Supporting

PS1 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.1501+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 7 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 7 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). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information (PMID: 19169489). Therefore, PP4 cannot be applied. The nucleotide change c.1501G>A is predicted to disrupt the intron 7 splice donor site to a similar extent as c.1501+1G>T, however, the c.1501+1G>A variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. Therefore, PS1_Supporting cannot be applied. In summary, c.1501+1G>T 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 is predicted to cause loss of function by resulting in nonsense mediated decay of a biologically relevant transcript.

PM2_Supporting

This variant is absent from gnomAD.

PS1

The nucleotide change c.1501G>A is predicted to disrupt the intron 7 splice donor site to a similar extent as c.1501+1G>T; however, the c.1501+1G>A variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP.

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to insufficient clinical information (PMID: 19169489).

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