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.1663C>T (p.Leu555Phe)

CA214281

36808 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8b920c00-cf31-40ef-a263-35e46162f466

HGVS expressions

NM_000545.6:c.1663C>T

NM_000545.6(HNF1A):c.1663C>T

NM_000545.6(HNF1A):c.1663C>T (p.Leu555Phe)

NC_000012.12:g.120999522C>T

CM000674.2:g.120999522C>T

NC_000012.11:g.121437325C>T

CM000674.1:g.121437325C>T

NC_000012.10:g.119921708C>T

NG_011731.2:g.25777C>T

ENST00000257555.11:c.1663C>T

ENST00000257555.10:c.1663C>T

ENST00000540108.1:c.*1103C>T

ENST00000541395.5:c.1756C>T

ENST00000543427.5:c.1126C>T

ENST00000544413.2:c.1684C>T

ENST00000560968.5:n.1480C>T

ENST00000615446.4:c.451C>T

ENST00000617366.4:c.*72C>T

NM_000545.5:c.1663C>T

NM_001306179.1:c.1684C>T

NM_000545.8:c.1663C>T

NM_001306179.2:c.1684C>T

NM_000545.8(HNF1A):c.1663C>T (p.Leu555Phe)

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

PM2_Supporting BS2 BP5

PS4 PP3

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.1663C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to phenylalanine at codon 555(p.(Leu555Phe)) of NM_000545.8. This variant has an allele frequency of 0.00001797 in Non- Finnish Europeans, below the MDEP threshold of 0.00002, and no copies in other subpopulations, in gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in the homozygous state in a 56 year old normoglycemic individual (BS2; PMID: 22341299). Lastly, this variant was identified in a patient with an alternate molecular basis for disease (BP5; PMID: 22341299). This variant was identified in one individual 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 (internal lab contributors). This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.1663C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PM2_Supporting, BS2, BP5.

PM2_Supporting

This variant has a minor allele frequency of 0.00001797 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting).

BS2

This variant was identified in a homozygous state in a 56 year-old normoglycemic individual (PMID:22341299) (BS2).

BP5

This variant has been observed in an individual with diabetes the variant c.659G>A (p.Cys220Tyr) in the glucokinase (GCK) gene (PMID: 22341299), which is classified as likely pathogenic by the ClinGen MDEP. (BP5).

PS4

This variant was identified in one individual 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 (internal lab contributors).

PP3

This variant has a REVEL score of 0.5809, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on HNF1A function.

Approved on: 2021-12-31

Published on: 2022-07-11

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