The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document

  • See Evidence submitted by expert panel for details.

Variant: NM_001306179.2:c.737T>C

CA386965866

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 41c877ea-0688-46fb-be79-b249f5d3f8fe
Approved on: 2021-08-18
Published on: 2021-10-29

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
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Uncertain Significance

Met criteria codes 5
PM2_Supporting BP5 PM1_Supporting PP3 PM5
Not Met criteria codes 1
PS4

Evidence Links 0

Expert Panel

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).
Met criteria codes
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)
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).
Not Met criteria codes
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).
Curation History
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