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.1424C>T (p.Pro475Leu)

CA214266

36801 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 06453332-f33d-4b0a-b752-4da92e9f78fd

Approved on: 2024-08-01

Published on: 2024-08-01

HGVS expressions

NM_000545.8:c.1424C>T

NM_000545.8(HNF1A):c.1424C>T (p.Pro475Leu)

NC_000012.12:g.120997588C>T

CM000674.2:g.120997588C>T

NC_000012.11:g.121435391C>T

CM000674.1:g.121435391C>T

NC_000012.10:g.119919774C>T

NG_011731.2:g.23843C>T

ENST00000560968.6:c.*171C>T

ENST00000257555.11:c.1424C>T

ENST00000257555.10:c.1424C>T

ENST00000400024.6:c.1424C>T

ENST00000402929.5:n.2290C>T

ENST00000535955.5:n.140C>T

ENST00000538626.2:n.288C>T

ENST00000538646.5:c.*400C>T

ENST00000540108.1:c.*864C>T

ENST00000541395.5:c.1424C>T

ENST00000541924.5:c.*438C>T

ENST00000543255.1:n.468C>T

ENST00000543427.5:c.887C>T

ENST00000544413.2:c.1424C>T

ENST00000544574.5:c.*187C>T

ENST00000560968.5:c.1241C>T

ENST00000615446.4:c.212C>T

ENST00000617366.4:c.587-46C>T

NM_000545.5:c.1424C>T

NM_000545.6:c.1424C>T

NM_001306179.1:c.1424C>T

NM_001306179.2:c.1424C>T

Uncertain Significance

BS2 PP4 PP3

BS1 PM2 PS4 BA1

Evidence Links 1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1424C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 475 (p.(Pro475Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.751, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, 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 at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 18811724, 23674172, internal lab contributors). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2: internal lab contributors). The frequency of the c.1424C>T variant in gnomAD v2.1.1 falls between the ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.1424C>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 2.1.0, approved 8/11/2023): PP3, PP4, BS2.

BS2

This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2: internal lab contributors).

PP4

This variant was present in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator score of greater than 50% and negative genetic testing for HNF4A).

Proband dx31 w T2DM, BMI 24.49, C-peptide 0.3; inclusion criteria for study: one FDR dx T2DM <35 and >2 generation FH of DM; tx w diet or oral agents, no DKA, no GAD AB PubMed:18811724

PP3

REVEL 0.751; SIFT, PolyPhen, LRT, MT, FATHMM, PROVEAN, MetaSVM, MetaLR all predict deleterious

BS1

Popmax filtering AF = 0.000007070 (ENF, AJ not included in Popmax filtering AF calculations) < 0.000033

PM2

Popmax filtering AF = 0.000007070 > 0.000003

PS4

This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs: 18811724, 23674172, internal lab contributors).

Proband dx31 w T2DM, BMI 24.49, C-peptide 0.3; inclusion criteria for study: one FDR dx T2DM <35 and >2 generation FH of DM; tx w diet or oral agents, no DKA, no GAD AB PubMed:18811724

BA1

Popmax filtering AF = 0.000007070 (ENF, AJ not included in Popmax filtering AF calculations) < 0.0001

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