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.815G>A (p.Arg272His)

CA124460

14931 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d5d2e5b3-43bd-4c42-a38d-791aad7cd241

HGVS expressions

NM_000545.6:c.815G>A

NM_000545.6(HNF1A):c.815G>A (p.Arg272His)

NC_000012.12:g.120994265G>A

CM000674.2:g.120994265G>A

NC_000012.11:g.121432068G>A

CM000674.1:g.121432068G>A

NC_000012.10:g.119916451G>A

NG_011731.2:g.20520G>A

ENST00000257555.11:c.815G>A

ENST00000257555.10:c.815G>A

ENST00000400024.6:c.815G>A

ENST00000402929.5:n.950G>A

ENST00000535955.5:n.43-3226G>A

ENST00000538626.2:n.191-3226G>A

ENST00000538646.5:c.628G>A

ENST00000540108.1:c.*255G>A

ENST00000541395.5:c.815G>A

ENST00000541924.5:c.713+559G>A

ENST00000543427.5:c.633+639G>A

ENST00000544413.2:c.815G>A

ENST00000544574.5:c.73-2352G>A

ENST00000560968.5:n.893+65G>A

ENST00000615446.4:c.-257-1997G>A

ENST00000617366.4:c.586+686G>A

NM_000545.5:c.815G>A

NM_001306179.1:c.815G>A

NM_000545.8:c.815G>A

NM_001306179.2:c.815G>A

NM_000545.8(HNF1A):c.815G>A (p.Arg272His)

Pathogenic

PS4 PP3 PM1 PM2_Supporting PS3_Supporting PP1_Strong

BA1 PM5 BS1 BS3 BP4

Evidence Links 13

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.815G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 272 (p.(Arg272His)) 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). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31166087, PMID:18003757, PMID:24905847, PMID:31483937, PMID:29439679, PMID:23610083, PMID:21989397, PMID:21395678, PMID:21224407, PMID:15114102, ClinVar ID 14931, internal lab contributors). This variant segregated with diabetes, with 13 informative meioses in multiple families with MODY (PP1_Strong; PMID:15114102, internal lab contributors). Functional studies demonstrated the p.Arg272His protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 16781669). In summary, c.815G>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): PP1_Strong, PS4, PM1, PP3, PM2_Supporting, PS3_Supporting.

PS4

This variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID:31166087, PMID:18003757, PMID:24905847, PMID:31483937, PMID:29439679, PMID:23610083, PMID:21989397, PMID:21395678, PMID:21224407, PMID:15114102, ClinVar ID 14931, internal lab contributors)

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater the MDEP VCEP threshold of 0.70 (PP3).

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.

Variant is located within helix 3 of the homeodomain DNA binding motif, a part of the domain strictly conserved among all known homeodomain sequences PubMed:15726414

PM2_Supporting

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

PS3_Supporting

Functional studies demonstrated the p.Arg272His protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:16781669).

Electrophoretic mobility shift assays (EMSA) showed the p.Arg272His variant has reduced DNA binding activity compared to the normal protein. PubMed:10585442

PP1_Strong

This variant segregated with disease with at least 13 informative meioses in multiple families with MODY (PP1_Strong; PMID:15114102, internal lab contributors).

Family G16, two generations confirmed segregation (can assume father (I-2) had it but he was not tested) PubMed:9032114

Parent-child segregation- six siblings with mutation, not all of younger ones have developed diabetes PubMed:11393552

Six individuals over two generations PubMed:15114102

Six individuals over two generations PubMed:9166684

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

The c.814C>A (p.Arg272Ser) and c.815G>A (p.Arg272Cys) variants have both been interpreted as pathogenic by the MDEP. p.Arg272His has the lowest Grantham score at this locus and was used as the base variant to apply PM5 to other variants at this locus, and therefore PM5 is not applied to p.Arg272His.

One Japanese patient (PS4) PubMed:16562587

Two patients (PS4) PubMed:18003757

p.Arg272Cys variant lacks DNA binding activity in EMSA and was shown to have no transactivation activity (PS3) PubMed:10333057

One UK patient (PS4) PubMed:28701371

Segregation in one Scandinavian family (PS4 and PP1) PubMed:10447526

One Italian patient (PS4) PubMed:25414397

Segregation in one Icelandic family (PS4 and PP1). De novo in father, maternity/paternity confirmed (PS2) PubMed:11719843

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-07-05

Published on: 2022-07-05

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