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

CA386954977

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 0faa6ae2-574e-4e61-bedd-c5ddf7e8ac27

HGVS expressions

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

Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PVS1 PS1_Supporting

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>C 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 was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate; internal lab contributors). The c.326+1G>A and c.326+1G>T variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>C has a similar predicted impact on donor loss by Splice AI (0.98) (PS1_Supporting). Lastly, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.326+1G>C 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, PS1_Supporting, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Absent from gnomAD.
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (internal lab contributors).
• PVS1: 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).
• PS1_Supporting: The c.326+1G>T and c.326+1G>A variants at the same canonical nucleotide have been classified as pathogenic for monogenic diabetes by the ClinGen MDEP, and c.326+1G>C has the same impact on donor loss predicted by Splice AI (0.98)

Approved on: 2022-06-10

Published on: 2022-06-10