Variant: NM_000545.8(HNF1A):c.19C>T (p.Gln7Ter)

CA386952237

562372 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 643c0bba-c736-4cd0-9d59-a247d1298b16

HGVS expressions

NM_000545.8:c.19C>T
NM_000545.8(HNF1A):c.19C>T (p.Gln7Ter)
NC_000012.12:g.120978787C>T
CM000674.2:g.120978787C>T
NC_000012.11:g.121416590C>T
CM000674.1:g.121416590C>T
NC_000012.10:g.119900973C>T
NG_011731.2:g.5042C>T
ENST00000257555.11:c.19C>T
ENST00000257555.10:c.19C>T
ENST00000400024.6:c.19C>T
ENST00000402929.5:n.154C>T
ENST00000535955.5:n.42+95C>T
ENST00000538626.2:n.137C>T
ENST00000538646.5:c.19C>T
ENST00000540108.1:c.19C>T
ENST00000541395.5:c.19C>T
ENST00000541924.5:c.19C>T
ENST00000543427.5:c.19C>T
ENST00000544413.2:c.19C>T
ENST00000544574.5:c.19C>T
ENST00000560968.5:n.162C>T
ENST00000615446.4:c.-258+76C>T
ENST00000617366.4:c.19C>T
NM_000545.5:c.19C>T
NM_000545.6:c.19C>T
NM_001306179.1:c.19C>T
NM_001306179.2:c.19C>T

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PS4_Moderate PP1_Strong

• Not Met criteria codes: PP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.19C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 7 (p.(Gln7Ter)) of NM_000545.8. This variant is located in exon 1 of 10, and is therefore predicted to result in nonsense mediated decay of a biologically relevant transcript 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). Additionally, this variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9097962, internal lab contributors). These cases were not tested for HNF4A; therefore, PP4 was not met. Lastly, this variant segregated with diabetes with at least ten informative meioses in three families with MODY (PP1_Strong; PMID 9097962; internal lab contributors). In summary, this variant 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, PS4_Moderate, PP1_Strong, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Absent in gnomAD v2.1
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4_Moderate: 3 independent families in Paris and one family from Vaxillarie 1997 (PMID 9097962)
• PP1_Strong: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Not Met criteria codes

• PP4: HNF4A not tested in available cases

Approved on: 2022-03-18

Published on: 2022-03-18