Submissions for variant NM_000341.4(SLC3A1):c.808C>T (p.Arg270Ter)

gnomAD frequency: 0.00019  dbSNP: rs200483989

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000332132	SCV000430661	pathogenic	Cystinuria	2017-04-28	criteria provided, single submitter	clinical testing	The SLC3A1 c.808C>T (p.Arg270Ter) variant has been reported in at least 11 individuals with cystinuria, including two siblings, in a homozygous state, and one individual in a compound heterozygous state (Pras et al. 1995; Endsley et al. 1997; Gitomet et al. 1998; Botzenhart et al. 2002; Chatzikyriakidou et al. 2005; Merieau et al. 2009). Four of the individuals homozygous for the p.Arg270Ter variant were of Ashkenazi Jewish ancestry (Pras et al. 1995). Control data are not available for the variant which is reported at a frequency of 0.00041 in the European (non-Finnish) population of the Exome Aggregation Consortium database. Based on the evidence and due to the potential impact of stop-gained variants, the p.Arg270Ter variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000332132	SCV001208284	pathogenic	Cystinuria	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg270*) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC3A1 are known to be pathogenic (PMID: 24610330, 25109415, 25964309). This variant is present in population databases (rs200483989, gnomAD 0.8%). This premature translational stop signal has been observed in individuals with cystinuria (PMID: 7539209, 28646536). ClinVar contains an entry for this variant (Variation ID: 336195). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000332132	SCV002811499	pathogenic	Cystinuria	2024-06-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000332132	SCV003821219	pathogenic	Cystinuria	2022-01-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001723928	SCV004183738	pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	SLC3A1: PVS1, PM2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000332132	SCV005398053	pathogenic	Cystinuria	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystinuria (MIM#220100). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with recessive disease, there are reports of affected carriers (PMID: 15635077, 25964309). (I) 0112 - The dominant condition associated with this gene has incomplete penetrance (PMID: 22480232). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (101 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and observed in homozygous and compound heterozygous individuals with cystinuria (ClinVar). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_000341.3(SLC3A1):c.2014_2015delinsTA; p.(Ala672*)) in a recessive disease. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV001723928	SCV005413326	pathogenic	not provided	2024-08-21	criteria provided, single submitter	clinical testing	PP4, PM3, PVS1
Reproductive Health Research and Development, BGI Genomics	RCV000332132	SCV001142317	pathogenic	Cystinuria	2020-01-06	no assertion criteria provided	curation	NM_000341.3:c.808C>T in the SLC3A1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Botzenhart E et al. identified this variant in two patients with cystinuria, including one in homozygous state amd one in compound heterozygous state (R270X/M467T) (PMID: 12234283 ). Gitomer WL et al. found this mutation in 3 patients in homozygous status, two were siblings (PMID: 9768685). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP4.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723928	SCV001957161	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723928	SCV001969701	pathogenic	not provided		no assertion criteria provided	clinical testing
Gene Friend Way, National Innovation Center	RCV003313951	SCV004013895	pathogenic	Autism spectrum disorder	2023-07-28	no assertion criteria provided	clinical testing	This sequence change creates a premature translational stop signal (p.Arg270*) in the SLC3A1 gene. It is expected to result in an absent or disrupted protein product which can manifest as kidney disease. In autism, there have been studies that show a link between ASD and kidney disease. PMID: 33340339. Mutations in SLC3A1 are known as the causative factor of cystinuria, which involving the defective transepithelial transport of cystine and the ability to reabsorb cystine into the blood (PMID: 25109415, 25964309). Meanwhile, plasma concentration of cystein is significantly decreased in ASD children (PMID: 15585776). In our study, an ASD patient carries this SLC3A1 rs200483989 mutation.
PreventionGenetics, part of Exact Sciences	RCV004754396	SCV005367498	pathogenic	SLC3A1-related disorder	2024-08-29	no assertion criteria provided	clinical testing	The SLC3A1 c.808C>T variant is predicted to result in premature protein termination (p.Arg270*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive cystinuria (Pras et al. 1995. PubMed ID: 7539209; Endsley et al. 1997. PubMed ID: 9186880; Botzenhart et al. 2002. PubMed ID: 12234283; Chatzikyriakidou et al. 2005. PubMed ID: 16225397; Tostivint et al. 2017. PubMed ID: 28646536) and has been reported to co-segregate with disease in at least one family (Gitomer et al. 1998. PubMed ID: 9768685). This variant is reported in 0.88% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been described as a possible founder variant (Pras et al. 1995. PubMed ID: 7539209). Nonsense variants in SLC3A1 are expected to be pathogenic. This variant is interpreted as pathogenic.