Submissions for variant NM_014669.5(NUP93):c.1162C>T (p.Arg388Trp)

gnomAD frequency: 0.00070  dbSNP: rs145146218

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000210641	SCV001164383	uncertain significance	Nephrotic syndrome, type 12	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Arg388Trp variant in NUP93 was identified by our study in one individual in the compound heterozygous state, with another VUS, with nephrotic syndrome. This variant was seen in 0.08230% (228/277052) of chromosomes, including one individual in the homozygous state, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145146218). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 224968). The p.Arg388Trp variant in NUP93 has been reported in one Serbian individual in the compound heterozygous state, with another missense variant reported pathogenic by OMIM in ClinVar (Variation ID: 224964), with nephrotic syndrome. In vitro functional studies with Xenopus laevis egg extracts and other assays provide some evidence that the p.Arg388Trp variant may impact nuclear pore complex formation and SMAD protein signalling (PMID: 26878725). However, these types of assays may not accurately represent biological function. In summary, the clinical significance of the p.Arg388Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PS3_Moderate (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV001532324	SCV001747834	likely pathogenic	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001532324	SCV001781668	likely pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrated that R388W mutant failed to restore nuclear envelope and NPC assembly when added back to Xenopus laevis egg extracts lacking NUP93 protein (Braun et al., 2016); 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: 30741391, 26878725, 29869118)
Invitae	RCV001532324	SCV002138362	uncertain significance	not provided	2023-12-10	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 388 of the NUP93 protein (p.Arg388Trp). This variant is present in population databases (rs145146218, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 26878725). ClinVar contains an entry for this variant (Variation ID: 224968). 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 NUP93 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NUP93 function (PMID: 26878725). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003417761	SCV004109343	uncertain significance	NUP93-related condition	2023-09-07	criteria provided, single submitter	clinical testing	The NUP93 c.1162C>T variant is predicted to result in the amino acid substitution p.Arg388Trp. This variant has been reported in the compound heterozygous state in a patient with steroid-resistant nephrotic syndrome, and segregated with disease in this family (Braun et al. 2016. PubMed ID: 26878725). In vitro functional studies indicated that this variant caused disrupted assembly of nuclear pore complex (Braun et al. 2016. PubMed ID: 26878725). However, this variant is reported in 0.13% of alleles in individuals of South Asian descent in gnomAD, including 1 homozygous individual (http://gnomad.broadinstitute.org/variant/16-56865830-C-T). In ClinVar, this variant has conflicting interpretations of pathogenicity ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/224968/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000210641	SCV000266819	pathogenic	Nephrotic syndrome, type 12	2020-11-20	no assertion criteria provided	literature only
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328162	SCV001449392	likely pathogenic	Nephrotic syndrome	2019-05-08	no assertion criteria provided	clinical testing	This individual is heterozygous for the c.1162C>T variant in the NUP93 gene, which results in the amino acid substitution of arginine to tryptophan at residue 388, p.(Arg388Trp). This variant has been reported as compound heterozygous with a second pathogenic NUP93 variant in an individual with steroid-resistant nephrotic sydrome (Braun et al 2016 Nat Genet. 48: 457-465). In vitro functional studies is supportive of a damaging effect from this amino acid change (Braun et al 2016). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.078% (221 out of 282,730 alleles including 1 homozygote). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all suggest that this variant is likely to be pathogenic. This variant is considered to be likely pathogenic according to the ACMG guidelines. (Evidence used: PS3, PM2, PM3, PP3)