Evidence Repository
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
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.

Variant: NM_001306179.2:c.383T>A

CA386959363

1327617 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 43562d19-0995-4085-a910-7729679c8403

HGVS expressions

NM_001306179.2:c.383T>A
NC_000012.12:g.120988889T>A
CM000674.2:g.120988889T>A
NC_000012.11:g.121426692T>A
CM000674.1:g.121426692T>A
NC_000012.10:g.119911075T>A
NG_011731.2:g.15144T>A
ENST00000257555.11:c.383T>A
ENST00000257555.10:c.383T>A
ENST00000400024.6:c.383T>A
ENST00000402929.5:n.518T>A
ENST00000535955.5:n.43-8602T>A
ENST00000538626.2:n.191-8602T>A
ENST00000538646.5:c.383T>A
ENST00000540108.1:c.327-4631T>A
ENST00000541395.5:c.383T>A
ENST00000541924.5:c.383T>A
ENST00000543427.5:c.383T>A
ENST00000544413.2:c.383T>A
ENST00000544574.5:c.73-7728T>A
ENST00000560968.5:n.526T>A
ENST00000615446.4:c.-257-7373T>A
ENST00000617366.4:c.383T>A
NM_000545.5:c.383T>A
NM_000545.6:c.383T>A
NM_001306179.1:c.383T>A
NM_000545.8:c.383T>A
NM_000545.8(HNF1A):c.383T>A (p.Ile128Asn)

Uncertain Significance

Met criteria codes 3
PM1_Supporting PM2_Supporting PP3
Not Met criteria codes 4
BS4 PS4 PP1 PM5

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.383T>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to asparagine at codon 128 (p.(Ile128Asn)) 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 is also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and 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: 9075819; PMID:15928245 cites PMID:9075819). It is unclear whether this variant segregates with diabetes in this individual's family; the variant is not found in the proband's diabetic mother and brother; however, it is found in the proband's diabetic son, and the proband's diabetic father and paternal family members were not tested (PMID 9075819). Additionally, another missense variant, c.382A>G (p.Ile128Val) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.383T>A 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 1.1, approved 6/4/2021): PP3, PM1_Supporting, PM2_Supporting.
Met criteria codes
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 (PM1_Supporting).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
Not Met criteria codes
BS4
It is unclear whether this variant segregates with diabetes in this individual's family; the variant is not found in the proband's diabetic mother and brother; however, it is found in the proband's diabetic son, and the proband's diabetic father and paternal family members were not tested (PMID 9075819).
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: 9075819; PMID:15928245 cites PMID:9075819).
PP1
It is unclear whether this variant segregates with diabetes in this individual's family; the variant is not found in the proband's diabetic mother and brother; however, it is found in the proband's diabetic son, and the proband's diabetic father and paternal family members were not tested (PMID 9075819).
PM5
Another missense variant, c.382A>G (p.Ile128Val) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.
Approved on: 2021-12-09
Published on: 2022-07-11
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