Variant: NM_000545.8(HNF1A):c.130del (p.Leu44fs)

CA214261

36798 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4fa9ddcb-687e-47a2-80ec-5c1d1073e80b

HGVS expressions

NM_000545.8:c.130del
NM_000545.8(HNF1A):c.130del (p.Leu44fs)
NC_000012.12:g.120978898del
CM000674.2:g.120978898del
NC_000012.11:g.121416701del
CM000674.1:g.121416701del
NC_000012.10:g.119901084del
NG_011731.2:g.5153del
ENST00000257555.11:c.130del
ENST00000257555.10:c.130del
ENST00000400024.6:c.130del
ENST00000402929.5:n.265del
ENST00000535955.5:n.42+206del
ENST00000538626.2:n.190+58del
ENST00000538646.5:c.130del
ENST00000540108.1:c.130del
ENST00000541395.5:c.130del
ENST00000541924.5:c.130del
ENST00000543427.5:c.130del
ENST00000544413.2:c.130del
ENST00000544574.5:c.72+58del
ENST00000560968.5:n.273del
ENST00000615446.4:c.-258+187del
ENST00000617366.4:c.130del
NM_000545.5:c.130del
NM_000545.6:c.130del
NM_001306179.1:c.130del
NM_001306179.2:c.130del

Pathogenic

• Met criteria codes: PM2_Supporting PP1_Strong PVS1 PP4

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.130delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 44 (NM_000545.8), adding 111 novel amino acids before encountering a stop codon (p.(Leu44TrpfsTer111)). This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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) (PP4; PMID: 15305805). This variant segregated with diabetes, with at least five informative meioses in two families with MODY (PP1_Strong; PMIDs: 15305805 and 12453976). 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 (PMIDs: 15305805 and 12453976). In summary, c.130delC 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, PM2_Supporting, PP1_Strong, PP4.

Met criteria codes

• PM2_Supporting: Absent from gnomAD.
• PP1_Strong: Segregated with diabetes, with at least five informative meioses in two families with MODY (PMIDs: 15305805 and 12453976).
• PVS1: This variant, located in biologically-relevant exon 1 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 23348805).
• PP4: Identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PMID: 15305805).

Not Met criteria codes

• PS4: Identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 15305805, 12453976).

Approved on: 2022-04-02

Published on: 2022-04-02