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_000545.8(HNF1A):c.1859C>T (p.Thr620Ile)

CA124466

14935 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5468a875-818b-44a1-b8cd-4e08577c4d5b

HGVS expressions

NM_000545.8:c.1859C>T

NM_000545.8(HNF1A):c.1859C>T (p.Thr620Ile)

NC_000012.12:g.121001155C>T

CM000674.2:g.121001155C>T

NC_000012.11:g.121438958C>T

CM000674.1:g.121438958C>T

NC_000012.10:g.119923341C>T

NG_011731.2:g.27410C>T

ENST00000257555.11:c.1859C>T

ENST00000257555.10:c.1859C>T

ENST00000288757.7:c.*2998G>A

ENST00000540108.1:c.*1299C>T

ENST00000541395.5:c.1952C>T

ENST00000543427.5:c.1322C>T

ENST00000544413.2:c.1880C>T

ENST00000560968.5:n.1676C>T

ENST00000615446.4:c.647C>T

ENST00000617366.4:c.*268C>T

NM_000545.5:c.1859C>T

NM_000545.6:c.1859C>T

NM_001306179.1:c.1880C>T

NM_001286191.2:c.*2998G>A

NM_001286196.2:c.*2998G>A

NM_001306179.2:c.1880C>T

NM_022895.3:c.*2998G>A

Uncertain Significance

PP1_Strong BS3_Supporting BS2 PM2_Supporting PP4

PS4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1859C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to isoleucine at codon 620 (p.Thr620Ile) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with 7 informative meioses in a single family with MODY (PP1_Strong; PMID: 10482964). Additionally, functional studies demonstrated the p.Thr620Ile protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 12530534) (BS3_Supporting). This variant was also identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (PMID: 10482964) (BS2). Lastly, 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) (PP4; internal lab contributors). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9075818, 25414397, 10482964, internal lab contributors). In summary, c.1859C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1 approved 9/30/2021): PM2_Supporting, PP1_Strong, BS3_Supporting, BS2, PP4.

PP1_Strong

This variant segregated with diabetes, with seven informative meioses in one family with MODY (internal lab contributors).

BS3_Supporting

Thomas 2002 (PMID: 12530534) reported transactivation activity equal to WT on HP1 construct (HNF1 binding site) and increased transactivation activity using HNF4A promoter construct. Authors suggested a possible a gain-of-function mutation. DNA binding was present (no quantification).

BS2

This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (PMID: 10482964).

PM2_Supporting

Absent from gnomAD.

PP4

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) (internal lab contributors).

PS4

This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 9075818, 25414397, 10482964, internal lab contributors).

Approved on: 2022-04-24

Published on: 2022-04-24

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