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_001306179.1:c.766T>A

CA6831829

998237 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 369be49a-2429-4e21-9a32-35ab1425ac6e

HGVS expressions

NM_001306179.1:c.766T>A

NC_000012.12:g.120994216T>A

CM000674.2:g.120994216T>A

NC_000012.11:g.121432019T>A

CM000674.1:g.121432019T>A

NC_000012.10:g.119916402T>A

NG_011731.2:g.20471T>A

ENST00000257555.11:c.766T>A

ENST00000257555.10:c.766T>A

ENST00000400024.6:c.766T>A

ENST00000402929.5:n.901T>A

ENST00000535955.5:n.43-3275T>A

ENST00000538626.2:n.191-3275T>A

ENST00000538646.5:c.579T>A

ENST00000540108.1:c.*206T>A

ENST00000541395.5:c.766T>A

ENST00000541924.5:c.713+510T>A

ENST00000543427.5:c.633+590T>A

ENST00000544413.2:c.766T>A

ENST00000544574.5:c.73-2401T>A

ENST00000560968.5:n.893+16T>A

ENST00000615446.4:c.-257-2046T>A

ENST00000617366.4:c.586+637T>A

NM_000545.5:c.766T>A

NM_000545.6:c.766T>A

NM_000545.8:c.766T>A

NM_001306179.2:c.766T>A

NM_000545.8(HNF1A):c.766T>A (p.Ser256Thr)

Likely Benign

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

BS3_Supporting BS1 PM1_Supporting PP3

PS4 PP4 PM2

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.766T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to threonine at codon 256 (p.Ser256Thr) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003551, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.782, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Ser256Thr protein has DNA binding above 50% of wild type and normal nuclear localization and transactivation, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 12574234). This variant was identified in three unrelated individuals 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: 12574234, internal lab contributors). One of these individuals had a calculated MODY probability <50%, and the MODY probability could not be calculated in the other two due to limited clinical information, and PP4 could not be applied. In summary, c.766T>A 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 9/30/2021): PM1_Supporting, BS1, PP3, BS3_Supporting.

BS3_Supporting

Bjorkhaug et al. (2003) demonstrated that cells with p.Ser256Thr variant had normal nuclear localization, higher than 50% of WT DNA binding activity, and similar transcriptional activity as WT.

BS1

This variant has a gnomAD European non-Finnish minor allele frequency greater than the MDEP cutoff of 0.000033 (actual value = 0.00003551).

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

PP3

REVEL 0.782 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Low, GERP score 4.84

PS4

This variant was identified in three unrelated individuals 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: 12574234, internal lab contributors).

PP4

Single case with low MODY probability calculator score (10%), and unable to use calculator for other reported cases.

PM2

This variant has a gnomAD European non-Finnish minor allele frequency greater than the cutoff of 0.00002 (actual value = 0.00003551).

Approved on: 2022-04-13

Published on: 2022-07-12

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.