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.812G>A (p.Arg271Gln)

CA6831835

449403 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 38c10de3-40b2-4def-bf4e-c08f9d43f223

HGVS expressions

NM_000545.6:c.812G>A

NM_000545.6(HNF1A):c.812G>A (p.Arg271Gln)

NC_000012.12:g.120994262G>A

CM000674.2:g.120994262G>A

NC_000012.11:g.121432065G>A

CM000674.1:g.121432065G>A

NC_000012.10:g.119916448G>A

NG_011731.2:g.20517G>A

ENST00000257555.11:c.812G>A

ENST00000257555.10:c.812G>A

ENST00000400024.6:c.812G>A

ENST00000402929.5:n.947G>A

ENST00000535955.5:n.43-3229G>A

ENST00000538626.2:n.191-3229G>A

ENST00000538646.5:c.625G>A

ENST00000540108.1:c.*252G>A

ENST00000541395.5:c.812G>A

ENST00000541924.5:c.713+556G>A

ENST00000543427.5:c.633+636G>A

ENST00000544413.2:c.812G>A

ENST00000544574.5:c.73-2355G>A

ENST00000560968.5:n.893+62G>A

ENST00000615446.4:c.-257-2000G>A

ENST00000617366.4:c.586+683G>A

NM_000545.5:c.812G>A

NM_001306179.1:c.812G>A

NM_000545.8:c.812G>A

NM_001306179.2:c.812G>A

NM_000545.8(HNF1A):c.812G>A (p.Arg271Gln)

Pathogenic

PS4 PP3 PM1 PM2_Supporting PP4_Moderate PP1_Strong

PS3 PM5

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.812G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 271 (p.(Arg271Gln) of NM_000545.8. This variant was identified in 19 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). 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). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.945, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Arg271Gln protein has DNA binding 110% of wild type and transactivation 50-60% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3 and BS3 (PMID: 26853433). The p.Arg271Trp and p.Arg271Gly variants have been interpreted as pathogenic and likely pathogenic, respectively, by the MDEP. Arg271Gln has a lower Grantham distance than both and was used as the base variant to apply PM5, and therefore, PM5 will not be applied to Arg271Gln. 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, PM1, PP3, PM2_Supporting, PP4_Moderate.

PS4

This variant was identified in 19 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

PP3

This variant is predicted to be deleterious by multiple lines of computational evidence with a REVEL score of 0.945.

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 the gnomAD European non-Finnish population, but one copy each is present in the East Asian and South Asian subpopulations.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfyonylurea-responsive) (internal lab contributors).

PP1_Strong

This variant segregated with diabetes, with four informative meioses in two families with MODY.

PS3

Increased DNA binding (110%), abnormal nuclear localization, reduced transactivation (50-60%) (PMID: 26853433).

PM5

The p.Arg271Trp and p.Arg271Gly variants have been interpreted as pathogenic and likely pathogenic, respectively, by the MDEP. Arg271Gln has a lower Grantham distance than both and was used as the base variant to apply PM5 and therefore, PM5 will not be applied to Arg271Gln.

Approved on: 2022-04-15

Published on: 2022-07-12

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