Variant: NM_001306179.2:c.326+1G>A

CA386954965

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 68847a9a-d3f2-43a5-a75d-7d926b70dba3

HGVS expressions

NM_001306179.2:c.326+1G>A
NC_000012.12:g.120979095G>A
CM000674.2:g.120979095G>A
NC_000012.11:g.121416898G>A
CM000674.1:g.121416898G>A
NC_000012.10:g.119901281G>A
NG_011731.2:g.5350G>A
ENST00000257555.11:c.326+1G>A
ENST00000257555.10:c.326+1G>A
ENST00000400024.6:c.326+1G>A
ENST00000402929.5:n.461+1G>A
ENST00000535955.5:n.42+403G>A
ENST00000538626.2:n.190+255G>A
ENST00000538646.5:c.326+1G>A
ENST00000540108.1:c.326+1G>A
ENST00000541395.5:c.326+1G>A
ENST00000541924.5:c.326+1G>A
ENST00000543427.5:c.326+1G>A
ENST00000544413.2:c.326+1G>A
ENST00000544574.5:c.72+255G>A
ENST00000560968.5:n.469+1G>A
ENST00000615446.4:c.-258+384G>A
ENST00000617366.4:c.326+1G>A
NM_000545.5:c.326+1G>A
NM_000545.6:c.326+1G>A
NM_001306179.1:c.326+1G>A
NM_000545.8:c.326+1G>A

Pathogenic

• Met criteria codes: PP4 PVS1 PP1_Strong PS1_Supporting PM2_Supporting

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.326+1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 1 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 1 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). Additionally, this variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributors). Lastly, the c.326+1G>T and c.326+1G>C variants at the same canonical nucleotides have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>A has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). In summary, c.326+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21):PVS1, PP1_Strong, PP4, PS1_Supporting, PM2_Supporting.

Met criteria codes

• PP4: This variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors).
• PVS1: Predicted to result in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism.
• PP1_Strong: This variant segregated with diabetes, with five informative meioses in one family with MODY (PP1_Strong; internal lab contributors).
• PS1_Supporting: The c.326+1G>T and c.326+1G>C variants at the same canonical nucleotides have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>A has the same predicted impact on donor loss by Splice AI (0.98).
• PM2_Supporting: Absent from gnomAD.

Not Met criteria codes

• PS4: This variant was identified in two unrelated individuals 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 (internal lab contributors).

Approved on: 2022-06-10

Published on: 2022-06-10