Submissions for variant NM_003982.4(SLC7A7):c.475C>T (p.Arg159Cys)

gnomAD frequency: 0.00011  dbSNP: rs11568437

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186169	SCV000239195	likely pathogenic	not provided	2014-03-03	criteria provided, single submitter	clinical testing	p.Arg159Cys (CGC>TGC): c.475 C>T in exon 3 of the SLC7A7 gene (NM_001126106.2). A R159C variant that is likely pathogenic was identified in the SLC7A7 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R159C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense mutation in a nearby residue (F152L) has been reported in association with lysinuric protein intolerance, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. Exon-level deletions of the SLC7A7 gene are a common cause of lysinuric protein intolerance in non-Finnish populations, likely due to recombination between Alu repeat elements (Font-LLitjos et al., 2009). Mutations in the SLC7A7 gene are associated with the autosomal recessive disorder lysinuric protein intolerance. The variant is found in UCD-MET panel(s).
Illumina Laboratory Services, Illumina	RCV000279372	SCV000385484	uncertain significance	Lysinuric protein intolerance	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000279372	SCV001064707	likely benign	Lysinuric protein intolerance	2024-01-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778777	SCV002014902	uncertain significance	not specified	2021-10-14	criteria provided, single submitter	clinical testing	Variant summary: SLC7A7 c.475C>T (p.Arg159Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248354 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC7A7 causing Lysinuric Protein Intolerance (0.00011 vs 0.0011), allowing no conclusion about variant significance. c.475C>T has been reported in the literature in an individual with early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an Lysinuric Protein Intolerance diagnosis was suspected post-mortem based on exome sequencing analysis, however, further analysis could not be performed (Contreras_2021). Additionally, the variation was reported to be enriched in the AJ population in comparison to reference populations in ExAC, which has a higher documented prevalence of Crohn's Disease. These reports do not provide unequivocal conclusions about association of the variant with Lysinuric Protein Intolerance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000279372	SCV002045724	uncertain significance	Lysinuric protein intolerance	2021-11-07	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262777	SCV002542953	uncertain significance	Autoinflammatory syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004020257	SCV004953714	uncertain significance	Inborn genetic diseases	2022-06-21	criteria provided, single submitter	clinical testing	The c.475C>T (p.R159C) alteration is located in exon 3 (coding exon 1) of the SLC7A7 gene. This alteration results from a C to T substitution at nucleotide position 475, causing the arginine (R) at amino acid position 159 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.