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_000545.8(HNF1A):c.620G>A (p.Gly207Asp)

CA386964424

447496 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9e82deb5-70f5-4b33-a7f6-22f6883030d8

HGVS expressions

NM_000545.8:c.620G>A

NM_000545.8(HNF1A):c.620G>A (p.Gly207Asp)

NC_000012.12:g.120993613G>A

CM000674.2:g.120993613G>A

NC_000012.11:g.121431416G>A

CM000674.1:g.121431416G>A

NC_000012.10:g.119915799G>A

NG_011731.2:g.19868G>A

ENST00000257555.11:c.620G>A

ENST00000257555.10:c.620G>A

ENST00000400024.6:c.620G>A

ENST00000402929.5:n.755G>A

ENST00000535955.5:n.43-3878G>A

ENST00000538626.2:n.191-3878G>A

ENST00000538646.5:c.527-551G>A

ENST00000540108.1:c.*60G>A

ENST00000541395.5:c.620G>A

ENST00000541924.5:c.620G>A

ENST00000543427.5:c.620G>A

ENST00000544413.2:c.620G>A

ENST00000544574.5:c.73-3004G>A

ENST00000560968.5:n.763G>A

ENST00000615446.4:c.-257-2649G>A

ENST00000617366.4:c.586+34G>A

NM_000545.5:c.620G>A

NM_000545.6:c.620G>A

NM_001306179.1:c.620G>A

NM_001306179.2:c.620G>A

Pathogenic

PM1_Supporting PM2_Supporting PS4_Moderate PP3 PP1_Strong PP4_Moderate

BA1 BS1 BP4

Evidence Links 5

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.620G>A variant in the HNF1 Homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 207 (p.(Gly207Asp)) of NM_000545.8. 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 response to low dose sulfonylurea) (PP4_Moderate). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate). Furthermore, this variant segregated with diabetes, with 10 informative meioses, in one family with MODY (PP1_Strong). The glycine at the 207 codon position is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.620G>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, PM1_Supporting, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3.

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

Figure 2 of the paper shows an alignment of murine HNF1A and HNF1B with depicted domains (11/27/18 MS) PubMed:1985954

"HNF-1α has been subdivided into three functional regions: an amino-terminal dimerization domain (residues 1–32), a DNA binding motif containing an atypical homeodomain (residues 203–276), and a carboxyl-terminal transactivation domain (residues 281–631) (Mendel and Crabtree, 1991)." The paper shows that G207 residue is located in the interface between POUS and POUH domains (figure 3) and that "Since every substitution at the interface perturbed transcriptional activity, we conclude that rigidity as opposed to flexibility between POUS and POUH domains of HNF1A is necessary for normal function." (11/27/18 MS) PubMed:12453420

PM2_Supporting

This variant is absent from gnomAD.

PS4_Moderate

This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 23674172, 21683639, 26479152, internal lab contributors).

One adult patient suspected to have MODY carried G207D. No segregation information. (HZ 11/26/2018) PubMed:21683639

Two patients from one family were reported to carry G207D. This paper only mentioned the family number, the patient number was obtained from another paper PMID:26479152. (HZ 11/26/2018) PubMed:16917892

One MODY patient reported to carry G207D. (HZ 11/26/2018) PubMed:23674172

PP3

REVEL 0.937, SIFT, PolyPhen, LRT, MT, FATHMM, PROVEAN, MetaSVM, MetaLR all predict pathogenicity

PP1_Strong

Variant segregated with disease with 10 informative meioses in a single family.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator score >50% and negative genetic testing for HNF4A), who also responded to a low dose of sulfonylureas.

BA1

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

BS1

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

BP4

REVEL 0.937, SIFT, PolyPhen, LRT, MT, FATHMM, PROVEAN, MetaSVM, MetaLR all predict pathogenicity

Approved on: 2022-06-10

Published on: 2022-06-10

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