Variant: NM_001306179.2:c.94G>T

CA386952811

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 15edf271-c906-4084-b3cc-c06dde9ff640

HGVS expressions

NM_001306179.2:c.94G>T
NC_000012.12:g.120978862G>T
CM000674.2:g.120978862G>T
NC_000012.11:g.121416665G>T
CM000674.1:g.121416665G>T
NC_000012.10:g.119901048G>T
NG_011731.2:g.5117G>T
ENST00000257555.11:c.94G>T
ENST00000257555.10:c.94G>T
ENST00000400024.6:c.94G>T
ENST00000402929.5:n.229G>T
ENST00000535955.5:n.42+170G>T
ENST00000538626.2:n.190+22G>T
ENST00000538646.5:c.94G>T
ENST00000540108.1:c.94G>T
ENST00000541395.5:c.94G>T
ENST00000541924.5:c.94G>T
ENST00000543427.5:c.94G>T
ENST00000544413.2:c.94G>T
ENST00000544574.5:c.72+22G>T
ENST00000560968.5:n.237G>T
ENST00000615446.4:c.-258+151G>T
ENST00000617366.4:c.94G>T
NM_000545.5:c.94G>T
NM_000545.6:c.94G>T
NM_001306179.1:c.94G>T
NM_000545.8:c.94G>T

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP4

• 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.94G>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 32 (p.(Glu32Ter)) of NM_000545.8. 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). 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; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in three 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 (PMID: 22802087, internal lab contributors). In summary, c.94G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting, PP4.

Met criteria codes

• PM2_Supporting: Absent from gnomAD
• 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: 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)(internal lab contributors).

Not Met criteria codes

• PS4: This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

Approved on: 2022-04-02

Published on: 2022-07-12