ClinVar Miner

Submissions for variant NM_014270.5(SLC7A9):c.997C>T (p.Arg333Trp)

gnomAD frequency: 0.00004  dbSNP: rs121908484
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801232 SCV000941001 pathogenic not provided 2023-05-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg333 amino acid residue in SLC7A9. Other variant(s) that disrupt this residue have been observed in individuals with SLC7A9-related conditions (PMID: 16609684, 28646536), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects SLC7A9 function (PMID: 11157794). 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 SLC7A9 protein function. ClinVar contains an entry for this variant (Variation ID: 5787). This missense change has been observed in individuals with autosomal recessive cystinuria (PMID: 11157794, 16138908, 16225397, 25296721, 25964309, 28717662). This variant is present in population databases (rs121908484, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the SLC7A9 protein (p.Arg333Trp).
Molecular Biology Laboratory, Fundació Puigvert RCV000006143 SCV001425264 likely pathogenic Cystinuria 2020-02-01 criteria provided, single submitter research
Revvity Omics, Revvity RCV000006143 SCV002020730 pathogenic Cystinuria 2021-06-17 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000006143 SCV002792687 pathogenic Cystinuria 2022-04-30 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000006143 SCV004047896 pathogenic Cystinuria criteria provided, single submitter clinical testing The SLC7A9 c.997C>T (p.Arg333Trp) variant has been observed in several individuals affected with cystinuria (Halbritter J et al, Chatzikyriakidou A et al). Experimental studies have shown that this missense change abolishes SLC7A9 cysteine transport (Font MA et al). This variant is reported with the allele frequency (0.0085%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Likely Pathogenic. The amino acid Arg at position 333 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg333Trp in SLC7A9 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003398451 SCV004118845 pathogenic SLC7A9-related disorder 2022-12-13 criteria provided, single submitter clinical testing The SLC7A9 c.997C>T variant is predicted to result in the amino acid substitution p.Arg333Trp. This variant was reported in the homozygous state in several individuals with cystinuria (ICC et al 2001. PubMed ID: 11157794; Chatzikyriakidou et al. 2005. PubMed ID: 16225397; Gaildrat P et al 2017. PubMed ID: 28717662) and compound heterozygous state in additional individuals with cystinuria (Halbritter J et al 2014. PubMed ID: 25296721; Rhodes et al. 2015. PubMed ID: 25964309). In addition, heterozygous carriers of this variant often show a phenotype of increased urinary excretion of cysteine and dibasic amino acids, which can lead to nephrolithiasis in some individuals (OMIM #220100; ICC et al 2001. PubMed ID: 11157794). Functional studies indicate the the p.Arg333Trp variant reduced cystine transport to only 10% of wild-type (ICC et al 2001. PubMed ID: 11157794). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-33334838-G-A). This variant is interpreted as pathogenic.
OMIM RCV000006143 SCV000026325 pathogenic Cystinuria 2001-02-15 no assertion criteria provided literature only

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