The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.


Variant: NM_001306179.1:c.142G>A

CA6831670

806957 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 6ac0c528-2d5f-409b-974e-99a40fe99e7e
Approved on: 2022-04-08
Published on: 2022-07-12

HGVS expressions

NM_001306179.1:c.142G>A
NC_000012.12:g.120978910G>A
CM000674.2:g.120978910G>A
NC_000012.11:g.121416713G>A
CM000674.1:g.121416713G>A
NC_000012.10:g.119901096G>A
NG_011731.2:g.5165G>A
ENST00000257555.11:c.142G>A
ENST00000257555.10:c.142G>A
ENST00000400024.6:c.142G>A
ENST00000402929.5:n.277G>A
ENST00000535955.5:n.42+218G>A
ENST00000538626.2:n.190+70G>A
ENST00000538646.5:c.142G>A
ENST00000540108.1:c.142G>A
ENST00000541395.5:c.142G>A
ENST00000541924.5:c.142G>A
ENST00000543427.5:c.142G>A
ENST00000544413.2:c.142G>A
ENST00000544574.5:c.72+70G>A
ENST00000560968.5:n.285G>A
ENST00000615446.4:c.-258+199G>A
ENST00000617366.4:c.142G>A
NM_000545.5:c.142G>A
NM_000545.6:c.142G>A
NM_000545.8:c.142G>A
NM_001306179.2:c.142G>A
NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys)
More

Likely Benign

Met criteria codes 2
BS1 BS3_Supporting
Not Met criteria codes 4
PM2 PS4 PP4 PP3

Evidence Links 0

Expert Panel

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.142G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to lysine at codon 48 (p.(Glu48Lys)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00009, which is greater than the MDEP threshold for BS1 (≥0.000033) (BS1). Functional studies demonstrated the p.Glu48Lys protein has normal nuclear localization, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 27899486). This variant was identified in at least 5 unrelated individuals with diabetes, but members of at least two families had evidence of autoimmunity; also, the variant does not meet the PM2_Supporting cutoff (PMID: 15928245, internal lab contributor). Therefore, PS4 could not be applied. This variant was not identified in any individuals with calculated MODY probability >=50%; therefore, PP4 could not be applied. In summary, c.142G>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 9/30/21): BS1, BS3_Supporting.
Met criteria codes
BS1
Popmax filtering AF ≥ 0.000033 with an exact value of 0.00009.
BS3_Supporting
Najmi et al. performed a luciferase assay (HeLa cells) that showed HNF1A E48K has 60% of transcriptional activity compared to wild type. Immunofluorescence assay detected HNF1A E48K has 80% nuclear localization compared to wild type (PMID 27899486).
Not Met criteria codes
PM2
Variant has a minor allele frequency in gnomAD of 0.00016 in ENF and 0.0005 in AJ subpopulations.
PS4
Identified in at least 5 unrelated individuals with diabetes, but members of at least two families had evidence of autoimmunity; also, the variant does not meet the PM2_Supporting cutoff (PMIDs: 15928245, internal lab contributors).
PP4
This variant was not identified in any individuals with calculated MODY probability >=50%.
PP3
REVEL = 0.691
Curation History
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