Variant: NM_001306179.2:c.526+1G>T

CA386960844

1746441 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 783da021-ae5d-40fd-8fc1-17103a557156

Approved on: 2023-12-02

Published on: 2023-12-02

HGVS expressions

NM_001306179.2:c.526+1G>T
NC_000012.12:g.120989033G>T
CM000674.2:g.120989033G>T
NC_000012.11:g.121426836G>T
CM000674.1:g.121426836G>T
NC_000012.10:g.119911219G>T
NG_011731.2:g.15288G>T
ENST00000257555.11:c.526+1G>T
ENST00000257555.10:c.526+1G>T
ENST00000400024.6:c.526+1G>T
ENST00000402929.5:n.661+1G>T
ENST00000535955.5:n.43-8458G>T
ENST00000538626.2:n.191-8458G>T
ENST00000538646.5:c.526+1G>T
ENST00000540108.1:c.327-4487G>T
ENST00000541395.5:c.526+1G>T
ENST00000541924.5:c.526+1G>T
ENST00000543427.5:c.526+1G>T
ENST00000544413.2:c.526+1G>T
ENST00000544574.5:c.73-7584G>T
ENST00000560968.5:c.669+1G>T
ENST00000615446.4:c.-257-7229G>T
ENST00000617366.4:c.526+1G>T
NM_000545.5:c.526+1G>T
NM_000545.6:c.526+1G>T
NM_001306179.1:c.526+1G>T
NM_000545.8:c.526+1G>T
NM_000545.8(HNF1A):c.526+1G>T

Pathogenic

• Met criteria codes: PS1_Supporting PM2_Supporting PVS1

• Not Met criteria codes: PP4 PP1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.526+1G>T variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 2 of NM_000545.8. This variant is predicted to cause loss of part of exon 2, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1, PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The HNF1A(NM_000545.8):c.526+1G>A and c.526+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>T has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33bp 65%) (PS1_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information.  This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP.  In summary, c.526+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): PVS1, PS1_Supporting, PM2_Supporting.    

Met criteria codes

• PS1_Supporting: The HNF1A(NM_000545.8):c.526+1G>A and c.526+1G>C variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.526+1G>T has a similar predicted impact by Splice AI (donor loss 100% and donor gain at -33 bp 65%) (PS1_Supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1.
• PVS1: This variant is predicted to cause loss of part exon 2 , leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism.

Not Met criteria codes

• PP4: This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information.
• PP1: This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP.