Variant: NM_001306179.1:c.811C>G

CA386966350

1338730 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4113fa42-f346-409e-a460-08c9200229e2

HGVS expressions

NM_001306179.1:c.811C>G
NC_000012.12:g.120994261C>G
CM000674.2:g.120994261C>G
NC_000012.11:g.121432064C>G
CM000674.1:g.121432064C>G
NC_000012.10:g.119916447C>G
NG_011731.2:g.20516C>G
ENST00000257555.11:c.811C>G
ENST00000257555.10:c.811C>G
ENST00000400024.6:c.811C>G
ENST00000402929.5:n.946C>G
ENST00000535955.5:n.43-3230C>G
ENST00000538626.2:n.191-3230C>G
ENST00000538646.5:c.624C>G
ENST00000540108.1:c.*251C>G
ENST00000541395.5:c.811C>G
ENST00000541924.5:c.713+555C>G
ENST00000543427.5:c.633+635C>G
ENST00000544413.2:c.811C>G
ENST00000544574.5:c.73-2356C>G
ENST00000560968.5:n.893+61C>G
ENST00000615446.4:c.-257-2001C>G
ENST00000617366.4:c.586+682C>G
NM_000545.5:c.811C>G
NM_000545.6:c.811C>G
NM_000545.8:c.811C>G
NM_001306179.2:c.811C>G
NM_000545.8(HNF1A):c.811C>G (p.Arg271Gly)

Likely Pathogenic

• Met criteria codes: PP3 PM1 PM5_Strong PM2_Supporting

• Not Met criteria codes: PP4

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.811C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 271 (p. (Arg271Trp) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). Two other missense variants, c.811C>T (p.Arg271Trp) and c.812G>A (p.Arg271Gln), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg271Gly has a greater Grantham distance than both p.Arg271Trp and p.Arg271Gln (PM5_Strong). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.911, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in two individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 was not applied (internal lab contributors). In summary, c.811C>G meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1, PM2_Supporting, PM5_Strong, PP3.

Met criteria codes

• PP3: Predicted deleterious with a REVEL score of 0.911.
• PM1: This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP.
• PM5_Strong: Two other missense variants, c.811C>T (p.Arg271Trp) and c.812G>A (p.Arg271Gln), have been interpreted as pathogenic by the ClinGen MDEP, and p.Arg271Gly has a greater Grantham distance than both p.Arg271Trp and p.Arg271Gln.
• PM2_Supporting: This variant is absent from gnomAD.

Not Met criteria codes

• PP4: This variant was identified in two individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors).

Approved on: 2022-04-14

Published on: 2022-07-12