Submissions for variant NM_000545.8(HNF1A):c.397G>A (p.Val133Met)

dbSNP: rs2135832611

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002260406	SCV002540103	likely pathogenic	Monogenic diabetes	2022-06-24	reviewed by expert panel	curation	The c.397G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 133 (p.(Val133Met)) 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 0.974, 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 at least five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 10754480, PMID 21170474, PMID 17573900, internal lab contributors). Due to lack of individual level data and/or lack of testing for HNF4A, PP4 could not be applied to any of these cases. This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID 10754480). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 21170474). In summary, the c.397G>A variant 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): PS4_Moderate, PP1, PP3, PM1_Supporting, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001976603	SCV002264388	likely pathogenic	not provided	2021-07-17	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A protein function (PMID: 21170474). 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. This variant has been observed in individual(s) with MODY, type III (PMID: 10754480). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 133 of the HNF1A protein (p.Val133Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine.