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_001306179.2:c.425C>A

CA386959897

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 70ff5b20-1f7f-496b-87c0-60b03dbe31f6

HGVS expressions

NM_001306179.2:c.425C>A

NC_000012.12:g.120988931C>A

CM000674.2:g.120988931C>A

NC_000012.11:g.121426734C>A

CM000674.1:g.121426734C>A

NC_000012.10:g.119911117C>A

NG_011731.2:g.15186C>A

ENST00000257555.11:c.425C>A

ENST00000257555.10:c.425C>A

ENST00000400024.6:c.425C>A

ENST00000402929.5:n.560C>A

ENST00000535955.5:n.43-8560C>A

ENST00000538626.2:n.191-8560C>A

ENST00000538646.5:c.425C>A

ENST00000540108.1:c.327-4589C>A

ENST00000541395.5:c.425C>A

ENST00000541924.5:c.425C>A

ENST00000543427.5:c.425C>A

ENST00000544413.2:c.425C>A

ENST00000544574.5:c.73-7686C>A

ENST00000560968.5:n.568C>A

ENST00000615446.4:c.-257-7331C>A

ENST00000617366.4:c.425C>A

NM_000545.5:c.425C>A

NM_000545.6:c.425C>A

NM_001306179.1:c.425C>A

NM_000545.8:c.425C>A

Uncertain Significance

PM1_Supporting PM2_Supporting PM5_Supporting PP4 PP3

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.425C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to tyrosine at codon 142 (p.(Ser142Tyr)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.425C>T, p.Ser142Phe, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser142Tyr (PM5_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an 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 contributor). This individual has a calculated MODY probability of <50%, however the presence of a moderate level of criteria (persistent C-peptide) allows the application of this criteria at a supporting level per the ClinGen MDEP's approval (PP4; internal lab contributor). Taken together, this evidence supports a classification of this variant as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PP3, PP4, PM1_Supporting, PM2_Supporting, PM5_Supporting.

PM1_Supporting

This variant is located within the DNA binding domain (codons 107-174) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PM2_Supporting

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

PM5_Supporting

Another missense variant, c.425C>T, p.Ser142Phe, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ser142Tyr (PM5_Supporting).

PP4

This variant was identified in an individual with diabetes with a calculated MODY probability of <50%, however the presence of a moderate level of criteria (persistent C-peptide) allows the application of this criteria at a supporting level per the ClinGen MDEP's approval (PP4; internal lab contributor).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than the MDEP threshold of 0.70 (PP3).

PS4

This variant was identified in an 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 contributor).

Approved on: 2021-08-24

Published on: 2021-10-29

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