Submissions for variant NM_000545.8(HNF1A):c.391C>T (p.Arg131Trp)

dbSNP: rs137853244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001794451	SCV002032342	pathogenic	Monogenic diabetes	2021-08-18	reviewed by expert panel	curation	The c.391C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 131 (p.(R131W)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP threshold of 0.70 (PP3). Another missense variant, c.392G>A (p.Arg131Gln) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg131Trp has an equal or greater Grantham distance. (PM5). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 44 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9166684, PMID:9075818, PMID:22060211, internal lab contributors). However, the MODY probability is unable to be calculated due to lack of clinical information (PMID:9166684, PMID:9075818, PMID:22060211 internal lab contributors). This variant segregated with disease with 11 informative meioses in six families with MODY (PP1_Strong, internal lab contributor). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0): PP1_Strong, PS4, PM1, PM5, PP3, PM2_Supporting).
GeneDx	RCV000441594	SCV000521025	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	Published functional studies suggest defective nuclear translocation with activity significantly decreased compared to wildtype (Bjorkhaug et al., 2003); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25306193, 23348805, 20393147, 11058894, 12453420, 21224407, 25837654, 16917892, 26669242, 22060211, 28410371, 17989309, 23624530, 24344913, 23517481, 9075818, 28324025, 27913849, 15928245, 12488961, 12453976, 36208030, 34746319, 18003757, 36567880, 9166684, 12574234)
Athena Diagnostics	RCV000441594	SCV000613612	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including a de novo case, and appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant reduced DNA binding, impaired transcriptional activation, and caused defect in subcellular localization (PMID: 12574234). The variant is located in a region that is considered important for protein function and/or structure.
Geisinger Clinic, Geisinger Health System	RCV000016081	SCV002562134	pathogenic	Maturity-onset diabetes of the young type 3	2022-08-02	criteria provided, single submitter	research	PP3, PM1, PM2, PM5, PS4, PP1_Strong
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464066	SCV002605532	pathogenic	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs137853244 with MODY3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000441594	SCV004295425	pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 131 of the HNF1A protein (p.Arg131Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young type III (MODY3) (PMID: 9166684, 25837654, 34746319). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14943). 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 not expected to disrupt HNF1A protein function with a negative predictive value of 80%. This variant disrupts the p.Arg131 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8945470). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000016081	SCV005400536	pathogenic	Maturity-onset diabetes of the young type 3	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with maturity-onset diabetes of the young type III (MIM#600496). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v4: 3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000016081	SCV000036349	pathogenic	Maturity-onset diabetes of the young type 3	2003-02-01	no assertion criteria provided	literature only