ClinVar Genomic variation as it relates to human health

Reported previously as a common variant associated with mild cystinuria, with both autosomal recessive and dominant inheritance described (Feliubadalo et al., 1999; Harnevik et al., 2003; Rhodes et al., 2015; Gaildrat et al., 2017; Tostivint et al., 2017); Reported with both type 1 and non-type 1 cystinuria, demonstrating reduced penetrance in heterozygotes (Font-Llitjos et al., 2005; Gaildrat et al., 2017); Suggested to be a mild variant with reduced activity that results in a trafficking defect, but no functional studies have been performed to confirm this hypothesis, and available functional studies demonstrate significant residual transporter activity comparable to wild-type (Font et al., 2001; Reig et al. 2002; Font-Llitjos et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 30487145, 25637381, 25109415, 12234930, 24123366, 11157794, 26990548, 12820697, 10471498, 15635077, 25964309, 28646536, 28717662, 25296721, 28812535, 31589614, 35923129, 35643372, 34805638, 11260385, 25777271)

The p.Ala182Thr variant in SLC7A9 has been reported in at least 15 heterozygous and >10 homozygous or compound heterozygous individual with non-type 1 cystinuria or cystinuria type B (Feliubadalo 1999 PMID: 10471498, Font 2001 PMID: 11157794, and Font-Llitjos 2005 PMID: 15635077, Rhodes 2015 PMID: 25964309, Tostivint 2017 PMID: 28646536). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 5782) and been identified in 0.4% (290/68028) of European chromosomes including 2 total homozygotes by gnomAD, (http://gnomad.broadinstitute.org v.3.1.2). In vitro functional studies suggest that the p.Ala182Thr variant may be a mild mutation with reduced activity (Font 2001 PMID: 11157794, Reig 2002 PMID: 12234930). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Pathogenic variants in SLC7A9 are associated with cystinuria type B an autosomal recessive manner, though heterozygous carriers may have an elevated risk for kidney stones and increased cysteine excretion (Font-Llitjos 2005 PMID: 15635077, Fattah 2014 PMID: 25383320). In summary, although additional studies are required to fully establish its clinical significance, the p.Ala182Thr variant is likely pathogenic for cystinuria type B in an autosomal recessive manner, though some heterozygous carriers may also be at increased risk for a milder phenotype. ACMG/AMP Criteria applied: PS4, PM3, PS3_supporting.

The c.544G>A (p.A182T) alteration is located in exon 5 (coding exon 4) of the SLC7A9 gene. This alteration results from a G to A substitution at nucleotide position 544, causing the alanine (A) at amino acid position 182 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.26% (727/282810) total alleles studied. The highest observed frequency was 0.61% (63/10368) of Ashkenazi Jewish alleles. This alteration has been reported in multiple unrelated patients with cystinuria, and both autosomal recessive and autosomal dominant inheritance have been described (Feliubadaló, 1999; Bisceglia, 2001; Font, 2001; Font-Llitjós, 2005; Halbritter, 2015; Rhodes, 2015). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

The SLC7A9 c.544G>A (p.Ala182Thr) variant has been reported as one of the four most common SLC7A9 variants associated with cystinuria and is associated with a mild phenotype. The p.Ala182Thr variant has been reported in six studies in which it is found in a total of at least 29 affected individuals including three in a homozygous state, two in a compound heterozygous state and 24 in a heterozygous state. One individual homozygous for the p.Ala182Thr variant also carried compound heterozygous variants in the SLC3A1 gene and four of the heterozygotes also carried a second SLC7A9 variant in cis (Feliubadalo et al. 1999; Font et al. 2001; Harnevik et al. 2003; Font-Llitjos et al. 2005; Rhodes et al. 2015; Halbritter et al. 2015). The p.Ala182Thr variant was detected in a heterozygous state in one of at least 150 control individuals and is reported at a frequency of 0.00477 in the European American population of the Exome Sequencing Project. The Ala182 residue is not highly conserved. Functional studies demonstrate that the p.Ala182Thr variant enzyme is expressed at similar levels to wild type and results in aberrant trafficking to the plasma membrane and approximately 60% of activity compared to wild type, which is consistent with its presentation with a mild phenotype (Feliubadalo et al. 1999; Font et al. 2001; Reig et al. 2002; Font-Llitjos et al. 2005). While cystinuria generally displays an autosomal recessive mode of inheritance, some heterozygous carriers of variants in the SLC7A9 gene have abnormal urinary amino acid patterns and an increased risk of kidney stones (Eggermann et al. 2012). Based on the collective evidence, the p.Ala182Thr variant is classified as a pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The SLC7A9 c.544G>A (p.A182T) variant has been reported as one of the four most common SLC7A9 variants found in patients with cystinuria type B and is associated with a mild phenotype (PMID: 11157794; 12239244; 15635077; 19782624; 25109415; 25964309).

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 182 of the SLC7A9 protein (p.Ala182Thr). This variant is present in population databases (rs79389353, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with non-type I cystinuria or cystinuria (PMID: 10471498, 11157794, 11260385, 15635077, 25109415, 25296721, 25964309, 28646536). ClinVar contains an entry for this variant (Variation ID: 5782). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This individual is heterozygous for the c.544G>A variant in the SLC7A9 gene, which results in the amino acid substitution of alanine to threonine at residue 182, p.(Ala182Thr). This variant has been widely reported to be disease causing in both heterozygous and compound heterozygous forms and is known to be one of the common mutations causing autosomal recessive cystinuria type I (Palaci­n et al 2005 Physiology (Bethesda) 20: 112-124). Functional studies showed that the p.Ala182Thr substitution reduced but did not completely abolish transport activity (International Cystinuria Consortium 2001 Hum Mol Genet 10: 305-316). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PS3, PS4, PM3).

The SLC7A9 c.544G>A variant is predicted to result in the amino acid substitution p.Ala182Thr. This variant has been reported in many individuals to be a mild pathogenic allele for autosomal recessive cystinuria (see for example Tostivint et al. 2017. PubMed ID: 28646536; Font et al. 2001. PubMed ID: 11157794; Feliubadaló et al. 1999. PubMed ID: 10471498; Cogal et al. 2021. PubMed ID: 34805638; https://omim.org/entry/604144). This variant is reported in 0.61% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.

NM_014270.4:c.544G>A in the SLC7A9 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Ala182Thr (NM_014270.4:c.544G>A) variant in SLC7A9 has been reported in at least 15 heterozygous, 2 homozygous, and 3 compound heterozygous individual with cystinuria type B or non-type 1 cystinuria (PMID: 10471498; 11157794; 15635077). In vitro functional studies suggest that the p.Ala182Thr variant may be a mild mutation with reduced activity (PMID: 11157794; 12234930 ). Pathogenic computational verdict because pathogenic predictions from DANN, M-CAP, MVP, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PM3_Strong, PP3.