Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.1:c.748C>T

CA386965917

972754 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6e8eafc1-1051-447d-8cd5-574da313694e

HGVS expressions

NM_001306179.1:c.748C>T

NC_000012.12:g.120994198C>T

CM000674.2:g.120994198C>T

NC_000012.11:g.121432001C>T

CM000674.1:g.121432001C>T

NC_000012.10:g.119916384C>T

NG_011731.2:g.20453C>T

ENST00000257555.11:c.748C>T

ENST00000257555.10:c.748C>T

ENST00000400024.6:c.748C>T

ENST00000402929.5:n.883C>T

ENST00000535955.5:n.43-3293C>T

ENST00000538626.2:n.191-3293C>T

ENST00000538646.5:c.561C>T

ENST00000540108.1:c.*188C>T

ENST00000541395.5:c.748C>T

ENST00000541924.5:c.713+492C>T

ENST00000543427.5:c.633+572C>T

ENST00000544413.2:c.748C>T

ENST00000544574.5:c.73-2419C>T

ENST00000560968.5:n.891C>T

ENST00000615446.4:c.-257-2064C>T

ENST00000617366.4:c.586+619C>T

NM_000545.5:c.748C>T

NM_000545.6:c.748C>T

NM_000545.8:c.748C>T

NM_001306179.2:c.748C>T

NM_000545.8(HNF1A):c.748C>T (p.Gln250Ter)

Pathogenic

PVS1 PS4_Moderate PM2_Supporting PP4_Moderate

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.748C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 250 (p.(Gln250Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 4 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). Additionally, this variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate, internal lab contributors). Lastly, this variant was identified in unrelated individuals from four different families with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 1244228, internal lab contributors). In summary, c.748C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PM2_Supporting, PP4_Moderate, PS4_Moderate.

PVS1

This variant is predicted to cause loss of function by resulting in the nonsense mediated decay of a biologically relevant exon.

PS4_Moderate

This variant was identified in individuals from four different families with a clinical picture consistent with monogenic diabetes.

PM2_Supporting

This variant has a minor allele frequency in gnomAD of less than 0.00002 in the European non-Finnish population (actual value = 0.000008862).

PP4_Moderate

This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%) who also responded to low dose sulfonylureas.

Approved on: 2021-12-30

Published on: 2021-12-30

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