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]

Variant: NM_001306179.1:c.814C>A

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386966358

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3891dc84-edbb-49e5-83a3-d456bf042a1e

Approved on: 2022-04-15

Published on: 2022-07-12

HGVS expressions

NM_001306179.1:c.814C>A

NC_000012.12:g.120994264C>A

CM000674.2:g.120994264C>A

NC_000012.11:g.121432067C>A

CM000674.1:g.121432067C>A

NC_000012.10:g.119916450C>A

NG_011731.2:g.20519C>A

ENST00000257555.11:c.814C>A

ENST00000257555.10:c.814C>A

ENST00000400024.6:c.814C>A

ENST00000402929.5:n.949C>A

ENST00000535955.5:n.43-3227C>A

ENST00000538626.2:n.191-3227C>A

ENST00000538646.5:c.627C>A

ENST00000540108.1:c.*254C>A

ENST00000541395.5:c.814C>A

ENST00000541924.5:c.713+558C>A

ENST00000543427.5:c.633+638C>A

ENST00000544413.2:c.814C>A

ENST00000544574.5:c.73-2353C>A

ENST00000560968.5:n.893+64C>A

ENST00000615446.4:c.-257-1998C>A

ENST00000617366.4:c.586+685C>A

NM_000545.5:c.814C>A

NM_000545.6:c.814C>A

NM_000545.8:c.814C>A

NM_001306179.2:c.814C>A

Pathogenic

PP1_Strong PP3 PM5_Strong PM1 PM2_Supporting

PS4 PP4

Evidence Links 0

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.814C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to serine at codon 272 (p.(Arg272Ser)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors). Two other missense variants, c.814C>T (p.Arg272Cys) and c.815G>A (p.Arg272His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg272Ser has a greater Grantham distance than p.Arg272His. (PM5_Strong). 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 (PMIDs: 31165087 and 18003757, internal lab contributors). One of these individuals had a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.814C>A 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): PM1, PM2_Supporting, PP3, PP1_Strong, PM5_Strong.

PP1_Strong

This variant segregated with diabetes, with five informative meioses in two families with MODY (PP1_Strong; internal lab contributors).

PP3

REVEL 0.949 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said low, GERP score 4.84

PM5_Strong

Two other missense variants, c.814C>T (p.Arg272Cys) and c.815G>A (p.Arg272His), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg272Ser has a greater Grantham distance than p.Arg272His.

PM1

This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP.

PM2_Supporting

This variant is absent from gnomAD.

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 (PMIDs: 31165087 and 18003757, internal lab contributors).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors).

Curation History

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