Variant: NM_000545.8(HNF1A):c.160C>T (p.Arg54Ter)

CA386953303

805632 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: b134b21e-7bec-494b-b2e1-866ae6cc7eab

HGVS expressions

NM_000545.8:c.160C>T
NM_000545.8(HNF1A):c.160C>T (p.Arg54Ter)
NC_000012.12:g.120978928C>T
CM000674.2:g.120978928C>T
NC_000012.11:g.121416731C>T
CM000674.1:g.121416731C>T
NC_000012.10:g.119901114C>T
NG_011731.2:g.5183C>T
ENST00000257555.11:c.160C>T
ENST00000257555.10:c.160C>T
ENST00000400024.6:c.160C>T
ENST00000402929.5:n.295C>T
ENST00000535955.5:n.42+236C>T
ENST00000538626.2:n.190+88C>T
ENST00000538646.5:c.160C>T
ENST00000540108.1:c.160C>T
ENST00000541395.5:c.160C>T
ENST00000541924.5:c.160C>T
ENST00000543427.5:c.160C>T
ENST00000544413.2:c.160C>T
ENST00000544574.5:c.72+88C>T
ENST00000560968.5:n.303C>T
ENST00000615446.4:c.-258+217C>T
ENST00000617366.4:c.160C>T
NM_000545.5:c.160C>T
NM_000545.6:c.160C>T
NM_001306179.1:c.160C>T
NM_001306179.2:c.160C>T

Pathogenic

• Met criteria codes: PP4_Moderate PVS1 PS4 PM2_Supporting PP1_Strong PS2_Moderate

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.160C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 54 (p.(Arg54Ter)) of NM_000545.8. This variant, located in biologically relevant exon 1/10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent in gnomAD v2.1.1. (PM2_Supporting). This variant was identified in 11 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID:21224407, PMID:24905847, PMID:25414397, PMID:26050565, ClinVar ID 805632, internal lab contributors). This variant was identified in an individual with a clinical picture highly specific for HNF1A-MODY (MODY probability calculator >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate, internal lab contributor). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with non-autoimmune diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor). This variant segregates with diabetes with 9 informative meioses in 5 families with diabetes (PP1_Strong; PMID:26050565, internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for HNF1A-MODY by the ClinGen MDEP (PVS1, PM2_Supporting, PS4, PP4_Moderate, PP1_Strong, PS2_Moderate).

Met criteria codes

• PP4_Moderate: This variant was identified in an individual with a clinical picture highly specific for HNF1A-MODY (MODY probability calculator >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate).
• PVS1: This variant, located in biologically relevant exon 1/10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PS4: This variant was identified in 11 unrelated individuals with non-autoimmune/insulin-dependent diabetes (PS4; PMID:21224407, PMID:24905847, PMID:25414397, PMID:26050565, ClinVar ID 805632, internal lab contributors).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1. (PM2_Supporting).
• PP1_Strong: This variant segregates with diabetes with 9 informative meioses in 5 families with diabetes (PP1_Strong; PMID:26050565, internal lab contributors)
• PS2_Moderate: This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with non-autoimmune diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (PS2_Moderate; internal lab contributor).

Approved on: 2021-12-28

Published on: 2021-12-28