Submissions for variant NM_001366110.1(PAX4):c.133C>T (p.Arg45Trp)

gnomAD frequency: 0.00151  dbSNP: rs35155575

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502142	SCV000596237	benign	not specified	2018-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001555013	SCV001776359	uncertain significance	not provided	2021-08-23	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect, specifically in vitro analyses illustrate a reduction in the PAX4-binding ability to target gene promoters (Mauvais-Jarvis et al., 2004); 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: 32801813, 15509590, 20981092)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502142	SCV002103633	likely benign	not specified	2022-02-20	criteria provided, single submitter	clinical testing
New York Genome Center	RCV002467494	SCV002764459	uncertain significance	Maturity-onset diabetes of the young type 9; Type 2 diabetes mellitus	2021-12-02	criteria provided, single submitter	clinical testing	The heterozygous missense variant c.133C>T (p.Arg45Trp) identified in exon 4 (of 12) of the PAX4 gene has been reported in a patient with Ketosis-prone diabetes (KPD), a rare form of type 2 diabetes, mostly observed in subjects of west Africans and African-Americans (PMID: 15509590). The variant has 0.004851 allele frequency in the African/African American subpopulation represented in the gnomAD(v3.1.2) database (201 heterozygous alleles. Additionally, one homozygous allele in the gnomADv2.1.1 database). This variant is reported as a Variant of Uncertain Significance and benign in the ClinVar database (Variation ID:13792). The variant affects a conserved residue (Arg45) located in the paired box domain of PAX4 gene (PMID: 15509590) and is predicted deleterious by multiple insilico prediction tools (CADD score = 27.9, REVEL score = 0.917). In vitro functional analyses of c.133C>T (p.Arg45Trp) suggested impaired PAX4-binding ability to target gene promoters (PMID: 15509590). Based on the available evidence, the c.133C>T (p.Arg45Trp) variant identified in the PAX4 gene is reported as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001555013	SCV003245712	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003223336	SCV003918807	uncertain significance	Hyperglycemia		criteria provided, single submitter	clinical testing	The p.Arg45Trp variant is predicted to substitute the arginine at position 45 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database.
OMIM	RCV000014802	SCV000035057	risk factor	Diabetes mellitus, ketosis-prone, susceptibility to	2004-12-15	no assertion criteria provided	literature only
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV001555013	SCV002525698	uncertain significance	not provided	2019-12-17	flagged submission	clinical testing	The p.Arg37Trp variant is predicted to substitute the arginine at position 37 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database.