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.798C>G

CA386966233

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 77ad4b7f-ad6e-4c53-aeb5-894531bf7ccf

HGVS expressions

NM_001306179.2:c.798C>G

NC_000012.12:g.120994248C>G

CM000674.2:g.120994248C>G

NC_000012.11:g.121432051C>G

CM000674.1:g.121432051C>G

NC_000012.10:g.119916434C>G

NG_011731.2:g.20503C>G

ENST00000257555.11:c.798C>G

ENST00000257555.10:c.798C>G

ENST00000400024.6:c.798C>G

ENST00000402929.5:n.933C>G

ENST00000535955.5:n.43-3243C>G

ENST00000538626.2:n.191-3243C>G

ENST00000538646.5:c.611C>G

ENST00000540108.1:c.*238C>G

ENST00000541395.5:c.798C>G

ENST00000541924.5:c.713+542C>G

ENST00000543427.5:c.633+622C>G

ENST00000544413.2:c.798C>G

ENST00000544574.5:c.73-2369C>G

ENST00000560968.5:n.893+48C>G

ENST00000615446.4:c.-257-2014C>G

ENST00000617366.4:c.586+669C>G

NM_000545.5:c.798C>G

NM_000545.6:c.798C>G

NM_001306179.1:c.798C>G

NM_000545.8:c.798C>G

Uncertain Significance

PM2_Supporting PM1_Supporting PP3

PM5 PS4 PP4

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.798C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to lysine at codon 266 (p.(Asn266Lys)) of NM_000545.8. This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, and PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:18003757, internal lab contributor). Another missense variant, c.797A>G p.(Asn266Ser) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, this evidence supports the classification of c.798C>G 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 8/18/21): PP3, PM1_Supporting, PM2_Supporting.

PM2_Supporting

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

PM1_Supporting

This variant is located within the DNA binding domain (codons 201-280) of HNF1A, which is defined as critical for the protein's function by the ClinGen MDEP (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.837, which is greater than the MDEP threshold of 0.70 (PP3).

PM5

Another missense variant, c.797A>G p.(Asn266Ser) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

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 (PMID:18003757, internal lab contributor).

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID:18003757, internal lab contributor).

Approved on: 2021-08-24

Published on: 2021-10-29

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