Submissions for variant NM_014270.5(SLC7A9):c.544G>A (p.Ala182Thr)

gnomAD frequency: 0.00238  dbSNP: rs79389353

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000006138	SCV000411416	pathogenic	Cystinuria	2017-09-29	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000480556	SCV000565579	uncertain significance	not provided	2023-04-24	criteria provided, single submitter	clinical testing	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)
Snyder Lab, Genetics Department, Stanford University	RCV000006138	SCV000853096	pathogenic	Cystinuria	2017-01-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000006138	SCV000893519	likely pathogenic	Cystinuria	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000006138	SCV000967642	likely pathogenic	Cystinuria	2017-04-05	criteria provided, single submitter	clinical testing	The p.Ala182Thr 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 (Feliubadalo 1999, Font 2001, and Font-Llitjos 2005). This variant has also been identified in 0.4% (534/126690) of European chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbS NP rs79389353) and reported in ClinVar (Variation ID#5782) as pathogenic or like ly pathogenic. In vitro functional studies suggest that the p.Ala182Thr variant may be a mild mutation with reduced activity (Font 2001 and Reig 2002 ). Pathoge nic variants in SLC7A9 are associated with cystinuria type B an autosomal recess ive manner, though heterozygous carriers may present with non-type 1 cystinuria, an autosomal-dominant disorder with incomplete penetrance for cystine lithiasis (Font-Llitjos 2005). In summary, although additional studies are required to fu lly establish its clinical significance, the p.Ala182Thr variant is likely patho genic for cystinuria type B in an autosomal recessive manner and non-type 1 cyst inuria in an autosomal dominant manner with incomplete penetrance. ACMG/AMP Crit eria applied: PS4, PS3_Moderate.
Invitae	RCV000480556	SCV001203665	likely pathogenic	not provided	2024-01-22	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 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.
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000006138	SCV001251461	likely pathogenic	Cystinuria		criteria provided, single submitter	research	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).
Revvity Omics, Revvity	RCV000006138	SCV002023583	likely pathogenic	Cystinuria	2023-07-06	criteria provided, single submitter	clinical testing
Arcensus	RCV000006138	SCV002564619	likely pathogenic	Cystinuria	2013-02-01	criteria provided, single submitter	clinical testing
OMIM	RCV000006138	SCV000026320	pathogenic	Cystinuria	2005-01-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000006138	SCV000190632	likely pathogenic	Cystinuria	2014-06-01	no assertion criteria provided	research
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000006138	SCV000223950	likely pathogenic	Cystinuria	2014-07-29	no assertion criteria provided	clinical testing
Reproductive Health Research and Development, BGI Genomics	RCV000006138	SCV001142486	pathogenic	Cystinuria	2020-01-06	no assertion criteria provided	curation	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.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV000006138	SCV001449447	pathogenic	Cystinuria	2019-08-30	no assertion criteria provided	clinical testing	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).