Submissions for variant NM_003982.4(SLC7A7):c.1402C>T (p.Arg468Ter)

gnomAD frequency: 0.00003  dbSNP: rs386833807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000049772	SCV001163742	pathogenic	Lysinuric protein intolerance		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000049772	SCV001391425	pathogenic	Lysinuric protein intolerance	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg468*) in the SLC7A7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the SLC7A7 protein. This variant is present in population databases (rs386833807, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with lysinuric protein intolerance (PMID: 18716612). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 56359). This variant disrupts a region of the SLC7A7 protein in which other variant(s) (p.Arg473*) have been determined to be pathogenic (PMID: 10655553, 28028301; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000049772	SCV002045729	pathogenic	Lysinuric protein intolerance	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000049772	SCV002781818	likely pathogenic	Lysinuric protein intolerance	2022-04-11	criteria provided, single submitter	clinical testing
GeneDx	RCV003324723	SCV004030993	likely pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation, as the last 44 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 25525159, 18716612, 30665703, 31980526, 29058386, 10655553, 28028301, 37107561)
Neuberg Centre For Genomic Medicine, NCGM	RCV000049772	SCV005042635	pathogenic	Lysinuric protein intolerance		criteria provided, single submitter	clinical testing	The stop gained c.1402C>Tp.Arg468Ter variant in SLC7A7 gene has been reported previously in compound heterozygous state in individuals affected with lysinuric protein intolerance Font-Llitjós M, et al., 2009. It has also been observed to segregate with disease in related individuals. The c.1402C>T variant has been reported with allele frequency of 0.002% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submissions. The nucleotide change c.1402C>T in SLC7A7 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal p.Arg468Ter in the SLC7A7 gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. Other variants in the same region p.Arg473* have been previously reported to be pathogenic Habib A,et al., 2016. For these reasons, this variant has been classified as Pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049772	SCV000082179	probable-pathogenic	Lysinuric protein intolerance		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049772	SCV002091167	likely pathogenic	Lysinuric protein intolerance	2021-08-09	no assertion criteria provided	clinical testing