Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825652 | SCV000967023 | uncertain significance | not specified | 2018-01-16 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala354Thr variant in SLC7A9 has been reported in at least 6 patients with cystinuria (Lec lerc 2002, Font-Llitjos 2005, Bisceglia 2010, Abe 2014, Rhodes 2015), 3 of whom had another variant (p.Ala182Thr) on the same copy of the SLC7A9 gene (in cis). However, carriers of only this variant, in the absence of p.Ala182Thr, excrete e levated levels of dibasic amino acids (Leclerc 2002, Abe 2014) and in vitro func tional studies provide evidence that the p.Ala354Thr variant has a more severe i mpact protein function than p.Ala182Thr (Font 2001, Reig 2002). This variant has also been identified in 3/126608 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Pathogenic variants in SLC 7A9 are associated with cystinuria type B an autosomal recessive manner, though heterozygous carriers may present with non-type 1 cystinuria, an autosomal-domin ant disorder with incomplete penetrance for cystine lithiasis (Font-Llitjos 2005 ). Computational prediction tools and conservation analysis suggest that the var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathog enic role, the clinical significance of the p.Ala354Thr variant is uncertain. AC MG/AMP Criteria applied: PM2; PM3; PP3; PS3_Supporting; PS4_Supporting. |
| Labcorp Genetics |
RCV002538223 | SCV003247511 | pathogenic | not provided | 2023-12-01 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 354 of the SLC7A9 protein (p.Ala354Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with cystinuria (PMID: 28646536, 33262960). ClinVar contains an entry for this variant (Variation ID: 667033). 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 not expected to disrupt SLC7A9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC7A9 function (PMID: 11157794, 12234930). For these reasons, this variant has been classified as Pathogenic. |