Submissions for variant NM_000545.8(HNF1A):c.320T>G (p.Leu107Arg)

dbSNP: rs2135820413

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810533	SCV002060001	likely pathogenic	Monogenic diabetes	2021-09-15	reviewed by expert panel	curation	The c.320T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to arginine at codon 107 (p.(Leu107Arg)) of NM_000545.8. This variant is located within the DNA binding domain (codons 107-174) 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 0.93, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1. (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 9166684). This variant segregated with diabetes with 15 informative meioses in this individual's family (PP1_Strong; PMID: 9166684). Another missense variant, c.319C>G (p.Leu107Val) has been interpreted as pathogenic by the ClinGen MDEP and p.Leu107Arg has an equal or greater Grantham distance (PM5). In summary, c.320T>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 1.0, approved 8/18/21): PP1_Strong, PM5, PP3, PM1_Supporting, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002541485	SCV003442042	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 107 of the HNF1A protein (p.Leu107Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young, type III (PMID: 9166684). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1334148). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317532	SCV004020725	pathogenic	Maturity onset diabetes mellitus in young	2023-06-09	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.320T>G (p.Leu107Arg) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, N-terminal (IPR006899) of the encoded protein sequence. This alters a highly conserved residue (HGMD) in which another missense variant (p.Leu107Ile) has been classified as likely pathogenic by a ClinGen expert panel. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230888 control chromosomes (gnomAD). c.320T>G has been reported in the literature in multiple related individuals affected with Maturity Onset Diabetes Of The Young 3, showing strong evidence of cosegregation with disease (Glucksmann_1997). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9166684, 10333057, 12453976). Two submitters, including a ClinGen expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.