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.1135C>A (p.Pro379Thr)

CA6831957

972818 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5e9bf84c-2966-4860-b31d-dcfac7afc62e

Approved on: 2023-08-14

Published on: 2023-08-14

HGVS expressions

NM_000545.8:c.1135C>A

NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr)

NC_000012.12:g.120996568C>A

CM000674.2:g.120996568C>A

NC_000012.11:g.121434371C>A

CM000674.1:g.121434371C>A

NC_000012.10:g.119918754C>A

NG_011731.2:g.22823C>A

ENST00000257555.11:c.1135C>A

ENST00000257555.10:c.1135C>A

ENST00000400024.6:c.1135C>A

ENST00000402929.5:n.1270C>A

ENST00000535955.5:n.43-923C>A

ENST00000538626.2:n.191-923C>A

ENST00000538646.5:c.*111C>A

ENST00000540108.1:c.*575C>A

ENST00000541395.5:c.1135C>A

ENST00000541924.5:c.*149C>A

ENST00000543255.1:n.179C>A

ENST00000543427.5:c.634-36C>A

ENST00000544413.2:c.1135C>A

ENST00000544574.5:c.73-49C>A

ENST00000560968.5:n.952C>A

ENST00000615446.4:c.-78C>A

ENST00000617366.4:c.587-1066C>A

NM_000545.5:c.1135C>A

NM_000545.6:c.1135C>A

NM_001306179.1:c.1135C>A

NM_001306179.2:c.1135C>A

Uncertain Significance

BS1 PM5_Supporting PP1_Strong PP4 PP3

BA1 BS2 BP4 PS4 PM2 PM1

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 for HNF1A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 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 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant 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): BS1, PP3, PP4, PP1_Strong, PM5_Supporting.

BS1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1).

PM5_Supporting

Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting).

PP1_Strong

This variant segregated with diabetes, with at least 4 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors).

PP4

This variant was identified in an individual MODY probability calculator result >50%, negative genetic testing for HNF4A (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3).

BA1

Popmax FAF = 0.00003898 < 0.0001

BS2

several cases but < 70 years old

BP4

REVEL = 0.967

PS4

This variant was identified in 13 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 21170474, 15657605, internal lab contributors).

PM2

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

PM1

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

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