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]

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Variant: NM_000545.6(HNF1A):c.811C>T (p.Arg271Trp)

CA10588544

265193 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b52c71ef-1a30-4439-b5ec-d4ec00c3c8a1

HGVS expressions

NM_000545.6:c.811C>T

NM_000545.6(HNF1A):c.811C>T (p.Arg271Trp)

NC_000012.12:g.120994261C>T

CM000674.2:g.120994261C>T

NC_000012.11:g.121432064C>T

CM000674.1:g.121432064C>T

NC_000012.10:g.119916447C>T

NG_011731.2:g.20516C>T

ENST00000257555.11:c.811C>T

ENST00000257555.10:c.811C>T

ENST00000400024.6:c.811C>T

ENST00000402929.5:n.946C>T

ENST00000535955.5:n.43-3230C>T

ENST00000538626.2:n.191-3230C>T

ENST00000538646.5:c.624C>T

ENST00000540108.1:c.*251C>T

ENST00000541395.5:c.811C>T

ENST00000541924.5:c.713+555C>T

ENST00000543427.5:c.633+635C>T

ENST00000544413.2:c.811C>T

ENST00000544574.5:c.73-2356C>T

ENST00000560968.5:n.893+61C>T

ENST00000615446.4:c.-257-2001C>T

ENST00000617366.4:c.586+682C>T

NM_000545.5:c.811C>T

NM_001306179.1:c.811C>T

NM_000545.8:c.811C>T

NM_001306179.2:c.811C>T

NM_000545.8(HNF1A):c.811C>T (p.Arg271Trp)

Pathogenic

PM5 PM1 PS4 PS3_Supporting PP1_Strong PM2_Supporting PP3 PP4_Moderate

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.811C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 271 (p.(Arg271Trp) of transcript, e.g. NM_000545.8. This variant was identified in over 26 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with at least four informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated the p.Arg271Trp protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 21170474) (PS3_Supporting). 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). Another missense variant, c. 812G>A (p.Arg271Gln), has been interpreted as pathogenic by the ClinGen MDEP and p. Arg271Trp has a greater Grantham distance (PM5). The variant was identified in at least 8 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate). This variant failed QC in gnomAD v2.1.1. The variant was absent other than two heterozygotes filtered out due to poor quality which even if real would place the frequency below the ClinGen MDEP cutoff for PM2_Supporting (PM2_Supporting). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). 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): PS4, PP1_Strong, PS3_Supporting, PM1, PM5, PP4_Moderate, PP3, PM2_Supporting.

PM5

Another missense variant, c.812G>A (p.Arg271Gln) has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg271Trp has a greater Grantham distance (PM5).

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.

PS4

This variant was identified in unrelated individuals from at least 26 families with a clinical picture consistent with monogenic diabetes (internal laboratory contributors).

PS3_Supporting

Functional in vitro studies demonstrated that cells with this variant showed impaired transactivation (four reporters), decreased DNA binding, 15-30% of wild type transactivation, and >50% of wild type DNA binding with both nuclear and cytoplasmic staining.

PP1_Strong

This variant segregated with disease with more than four informative meioses in multiple families with MODY.

PM2_Supporting

This variant failed QC in gnomAD v2.1.1. The variant was absent other than two heterozygotes filtered out due to poor quality which even if real would place the frequency below the ClinGen MDEP cutoff for PM2_Supporting.

PP3

This variant is predicted to be deleterious by multiple lines of computational evidence with a REVEL score of 0.93.

PP4_Moderate

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 negative antibodies).

Approved on: 2022-04-14

Published on: 2022-07-12

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