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_001306179.2:c.737T>C

CA386965866

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 41c877ea-0688-46fb-be79-b249f5d3f8fe

HGVS expressions

NM_001306179.2:c.737T>C

NC_000012.12:g.120994187T>C

CM000674.2:g.120994187T>C

NC_000012.11:g.121431990T>C

CM000674.1:g.121431990T>C

NC_000012.10:g.119916373T>C

NG_011731.2:g.20442T>C

ENST00000257555.11:c.737T>C

ENST00000257555.10:c.737T>C

ENST00000400024.6:c.737T>C

ENST00000402929.5:n.872T>C

ENST00000535955.5:n.43-3304T>C

ENST00000538626.2:n.191-3304T>C

ENST00000538646.5:c.550T>C

ENST00000540108.1:c.*177T>C

ENST00000541395.5:c.737T>C

ENST00000541924.5:c.713+481T>C

ENST00000543427.5:c.633+561T>C

ENST00000544413.2:c.737T>C

ENST00000544574.5:c.73-2430T>C

ENST00000560968.5:n.880T>C

ENST00000615446.4:c.-257-2075T>C

ENST00000617366.4:c.586+608T>C

NM_000545.5:c.737T>C

NM_000545.6:c.737T>C

NM_001306179.1:c.737T>C

NM_000545.8:c.737T>C

Uncertain Significance

PM5 PM2_Supporting BP5 PM1_Supporting PP3

PS4

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.737T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to alanine at codon 246 (p.(V246A)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.847, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.736G>T (p.Val246Leu) has been interpreted as pathogenic by the ClinGen MDEP and p.Val246Ala has an equal or greater Grantham distance (PM5). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and 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 (internal lab contributors). In one of these individuals, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor). Taken together, this evidence supports the classification of c.737T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PM5, BP5, PP3, PM1_supporting, PM2_supporting).

PM5

Another missense variant, c.736G>T (p.Val246Leu) has been interpreted as pathogenic by the ClinGen MDEP and p.Val246Ala has an equal or greater Grantham distance (PM5).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

BP5

This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributor).

PM1_Supporting

This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.847, which is greater than the MDEP threshold of 0.70 (PP3)

PS4

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 (internal lab contributors).

Approved on: 2021-08-18

Published on: 2021-10-29

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