Variant: NM_001306179.2:c.25C>T

CA386952304

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: b6fb454e-fcba-4c22-98ae-bc50d72918f3

HGVS expressions

NM_001306179.2:c.25C>T
NC_000012.12:g.120978793C>T
CM000674.2:g.120978793C>T
NC_000012.11:g.121416596C>T
CM000674.1:g.121416596C>T
NC_000012.10:g.119900979C>T
NG_011731.2:g.5048C>T
ENST00000257555.11:c.25C>T
ENST00000257555.10:c.25C>T
ENST00000400024.6:c.25C>T
ENST00000402929.5:n.160C>T
ENST00000535955.5:n.42+101C>T
ENST00000538626.2:n.143C>T
ENST00000538646.5:c.25C>T
ENST00000540108.1:c.25C>T
ENST00000541395.5:c.25C>T
ENST00000541924.5:c.25C>T
ENST00000543427.5:c.25C>T
ENST00000544413.2:c.25C>T
ENST00000544574.5:c.25C>T
ENST00000560968.5:n.168C>T
ENST00000615446.4:c.-258+82C>T
ENST00000617366.4:c.25C>T
NM_000545.5:c.25C>T
NM_000545.6:c.25C>T
NM_001306179.1:c.25C>T
NM_000545.8:c.25C>T

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PS4_Moderate

• Not Met criteria codes: PP4

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.25C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 9 (p.(Gln9Ter)) 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 24905847, 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 9/30/2021): PVS1, PM2_Supporting, PS4_Moderate.

Met criteria codes

• PM2_Supporting: The variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• 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 (PVS1; PMID: 23348805).
• PS4_Moderate: This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; [PMID: 24905847, internal lab contributors]).

Not Met criteria codes

• PP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-03-25

Published on: 2022-07-12