Variant: NM_000545.8(HNF1A):c.29C>T (p.Thr10Met)

CA6831654

435422 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 8ef86fda-d3aa-499f-b2c7-b048f46262cb

Approved on: 2022-03-28

Published on: 2022-07-12

HGVS expressions

NM_000545.8:c.29C>T
NM_000545.8(HNF1A):c.29C>T (p.Thr10Met)
NC_000012.12:g.120978797C>T
CM000674.2:g.120978797C>T
NC_000012.11:g.121416600C>T
CM000674.1:g.121416600C>T
NC_000012.10:g.119900983C>T
NG_011731.2:g.5052C>T
ENST00000257555.11:c.29C>T
ENST00000257555.10:c.29C>T
ENST00000400024.6:c.29C>T
ENST00000402929.5:n.164C>T
ENST00000535955.5:n.42+105C>T
ENST00000538626.2:n.147C>T
ENST00000538646.5:c.29C>T
ENST00000540108.1:c.29C>T
ENST00000541395.5:c.29C>T
ENST00000541924.5:c.29C>T
ENST00000543427.5:c.29C>T
ENST00000544413.2:c.29C>T
ENST00000544574.5:c.29C>T
ENST00000560968.5:n.172C>T
ENST00000615446.4:c.-258+86C>T
ENST00000617366.4:c.29C>T
NM_000545.5:c.29C>T
NM_000545.6:c.29C>T
NM_001306179.1:c.29C>T
NM_001306179.2:c.29C>T

Uncertain Significance

• Met criteria codes: PM1_Supporting PM5_Supporting PP4

• Not Met criteria codes: PS4

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.29C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 10 (p.(Thr10Met)) of NM_000545.8. This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  Additionally, this variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). While the variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate could not be applied because c.29C>T does not meet the criteria to apply PM2_Supporting (≤0.00002 allele frequency in the European Non-Finnish population and ≤1 copy in any other subpopulation)(PMIDs 30155490, 18003757, internal lab contributors). Another missense variant, c.28A>C (p.Thr10Pro) has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this variant 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 9/30/21): PM1_Supporting, PP4, PM5_Suppporting.

Met criteria codes

• PM1_Supporting: In the dimerization domain (codons 1-32)
• PM5_Supporting: p.Thr10Pro is LP, Thr-Met Grantham distance = 81 which is greater than Thr-Pro Grantham distance of 38
• PP4: Patient MODY probability calculator score >50% and HNF4A-variant negative

Not Met criteria codes

• PS4: At least 5 unrelated cases with with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant MAF in gnomAD 2.1.1 is above the MDEP PM2_Supporting cutoff.