Submissions for variant NM_014270.5(SLC7A9):c.614dup (p.Asn206fs)

dbSNP: rs745319034

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000788761	SCV000342240	pathogenic	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000286788	SCV000411414	pathogenic	Cystinuria	2017-04-28	criteria provided, single submitter	clinical testing	The SLC7A9 c.614dupA (p.Asn206GlufsTer3) variant, also referred to as c.799insA, has been reported in five studies in a total of 33 individuals with cystinuria, including three homozygotes, eight compound heterozygotes, and 22 heterozygotes with varying disease types (Leclerc et al. 2002; Font-Llitjos et al. 2005; Barbosa et al. 2012; Rhodes et al. 2015; Halbritter et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Asn206GlufsTer3 variant results in a frameshift, and is predicted to truncate the protein. 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 evidence and due to the potential impact of frameshift variants, the p.Asn206GlufsTer3 variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV000788761	SCV000927996	pathogenic	not provided	2018-10-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000788761	SCV000950666	pathogenic	not provided	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn206Glufs*3) in the SLC7A9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC7A9 are known to be pathogenic (PMID: 11157794, 16838140, 25296721). This variant is present in population databases (rs745319034, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cystinuria in the heterozygous state (PMID: 12371955, 15635077, 16834950, 19782624, 21255007, 25109415, 25296721, 25964309). It has also been observed to segregate with disease in related individuals. This variant is also known as 799insA and c.800-801insA. ClinVar contains an entry for this variant (Variation ID: 288197). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000286788	SCV000966984	pathogenic	Cystinuria	2017-09-15	criteria provided, single submitter	clinical testing	The p.Asn206GlufsX3 (NM_014270.4 c.614dupA) variant in SLC7A9 (also referred to as c.799insA or c.800?801insA in the literature) has been reported in at least 2 5 heterozygotes, 2 homozygotes, and 2 compound heterozygotes with cystinuria (Le clerc 2002, Font-Llitjos 2005, Barbosa 2012, Rhodes 2015, and Halbritter 2015). Twenty one heterozygotes were noted to have non-type I cystinuria (heterozygotes with moderate to high excretion of cystine in urine and risk of forming urinary tract stones) (Font-Llitjos 2005, Barbosa 2012, Halbritter 2015). This variant has also been reported in ClinVar (Variation ID#288197), as pathogenic by two la boratories. It has been identified in 0.024% (30/126,648) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs745319034). This variant is predicted to cause a frameshift, which alte rs the protein?s amino acid sequence beginning at position 206 and leads to a pr emature termination codon 3 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Loss of function of the SLC7A9 g ene is an established disease mechanism in cystinuria. Variants associated with non-type I cystinuria, such as this variant, are inherited in an autosomal domin ant manner with incomplete penetrance and cause more severe disease in the homoz ygous or compound heterozygous state. In summary, although additional studies a re required to fully establish its clinical significance, the p.Asn206GlufsX3 va riant is pathogenic for cystinuria in an autosomal dominant manner with incompl ete penetrance based on its occurrence in affected individuals and a predicted n ull effect.
Fulgent Genetics, Fulgent Genetics	RCV000286788	SCV001752556	pathogenic	Cystinuria	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000788761	SCV002015431	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients from different ethnic backgrounds with type II and type III cystinuria or with cystinuria and nephrolithiasis in published literature (PMID: 25296721, 12371955); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 12371955, 26990548, 25296721, 30609409, 29431110, 37279760, 28717662)
Revvity Omics, Revvity	RCV000286788	SCV002020729	pathogenic	Cystinuria	2023-11-16	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000286788	SCV005398832	pathogenic	Cystinuria	2024-10-08	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. Some heterozygous variants have been reported to present with a milder phenotype (OMIM, PMID: 11157794). (I) 0112 - The condition associated with this gene has incomplete penetrance. Autosomal dominant cystinuria has been reported to have incomplete penetrance (PMID: 25964309). (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 <0.01 (v2: 41 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 classified as pathogenic by clinical laboratories (ClinVar), and has been observed as heterozygous, compound heterozygous and homozygous variants in multiple unrelated individuals with cystinuria (PMID: 12379955; 25964309; 28646536) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center	RCV000286788	SCV005900099	pathogenic	Cystinuria	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_SUP,PM2_SUP
OMIM	RCV000286788	SCV000026328	pathogenic	Cystinuria	2002-11-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003417906	SCV004107695	pathogenic	SLC7A9-related disorder	2023-11-30	no assertion criteria provided	clinical testing	The SLC7A9 c.614dupA variant is predicted to result in a frameshift and premature protein termination (p.Asn206Glufs*3). This common pathogenic SLC7A9 variant in the heterozygous state has been reported to cause moderate or severe cystinuria in different families, suggesting an autosomal dominant mode of inheritance (reported as 799insA at Leclerc et al. 2002. PubMed ID: 12371955). This variant has also been reported in the homozygous or compound heterozygous state in many unrelated individuals to cause cystinuria (Rhodes et al. 2015. PubMed ID: 25964309; Bisceglia et al. 2010. PubMed ID: 19782624; Barbosa et al. 2011. PubMed ID: 21255007). In summary, the c.614dup is classified as pathogenic.