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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000545.6(HNF1A):c.803T>C (p.Phe268Ser)

CA214330

36831 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6fcf1304-1a2d-416e-9805-3e69f6fdd22a

HGVS expressions

NM_000545.6:c.803T>C

NM_000545.6(HNF1A):c.803T>C (p.Phe268Ser)

NC_000012.12:g.120994253T>C

CM000674.2:g.120994253T>C

NC_000012.11:g.121432056T>C

CM000674.1:g.121432056T>C

NC_000012.10:g.119916439T>C

NG_011731.2:g.20508T>C

ENST00000257555.11:c.803T>C

ENST00000257555.10:c.803T>C

ENST00000400024.6:c.803T>C

ENST00000402929.5:n.938T>C

ENST00000535955.5:n.43-3238T>C

ENST00000538626.2:n.191-3238T>C

ENST00000538646.5:c.616T>C

ENST00000540108.1:c.*243T>C

ENST00000541395.5:c.803T>C

ENST00000541924.5:c.713+547T>C

ENST00000543427.5:c.633+627T>C

ENST00000544413.2:c.803T>C

ENST00000544574.5:c.73-2364T>C

ENST00000560968.5:n.893+53T>C

ENST00000615446.4:c.-257-2009T>C

ENST00000617366.4:c.586+674T>C

NM_000545.5:c.803T>C

NM_001306179.1:c.803T>C

NM_000545.8:c.803T>C

NM_001306179.2:c.803T>C

NM_000545.8(HNF1A):c.803T>C (p.Phe268Ser)

Likely Pathogenic

PM1_Supporting PM2_Supporting PS2_Moderate PS4_Moderate PP3

PP4 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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.803T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of phenylalanine to serine at codon 268 (p.(Phe268Ser)) of NM_000545.8. This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.986 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), but was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributor). The MODY probability is unable to be calculated due to lack of clinical information (PMID: 27634015, PMID: 15305805). This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PS2_Moderate; internal lab contributor). Two other missense variants, c.802T>A p.(Phe268Ile) and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied. In summary, the evidence supports the classification of c.803T>C as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 8/18/2021): PS2_moderate, PS4_moderate, PP3, PM1_Supporting, PM2_Supporting.

PM1_Supporting

This variant is located within the DNA binding domain of HNF1A (codons 201-280), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PM2_Supporting

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

PS2_Moderate

This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A) (PS2_Moderate; internal lab contributor).

PS4_Moderate

This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27634015, PMID: 15305805, ClinVar ID 36831, internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, which is greater than the MDEP threshold of 0.70 (PP3).

PP4

This variant was identified in two individuals with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information (PMID: 27634015, PMID: 15305805).

PM5

Two other missense variants, c.802T>A p.(Phe268Ile) and c.802T>C p.(Phe268Leu) do not meet the criteria to be classified as likely pathogenic or pathogenic by the ClinGen MDEP without the addition of PM5 from this variant; therefore, PM5 will not be applied.

Approved on: 2021-12-09

Published on: 2022-07-11

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