Submissions for variant NM_014270.5(SLC7A9):c.671C>T (p.Ala224Val)

gnomAD frequency: 0.00006  dbSNP: rs140873167

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778542	SCV000914834	pathogenic	Cystinuria	2018-10-10	criteria provided, single submitter	clinical testing	The SLC7A9 c.671C>T (p.Ala224Val) variant has been reported in three studies in a total of nine probands with cystinuria including one in a homozygous state, three in a compound heterozygous state, and five in a heterozygous state without a second allele identified (Botzenhart et al. 2002, Rhodes et al. 2015, Halbritter et al. 2015). The p.Ala224Val variant was also found in one unaffected parent in a heterozygous state (Botzenhart et al. 2002). There is evidence that cystinuria type B can be inherited in an autosomal dominant pattern with incomplete penetrance or an autosomal recessive pattern (Barbosa et al. 2012). The p.Ala224Val variant was absent from at least 50 control samples and is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. 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, the p.Ala224Val variant is classified as pathogenic for cystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000778542	SCV002799560	likely pathogenic	Cystinuria	2024-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002536733	SCV003293453	pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 224 of the SLC7A9 protein (p.Ala224Val). This variant is present in population databases (rs140873167, gnomAD 0.007%). This missense change has been observed in individual(s) with cystinuria (PMID: 12234283, 19782624, 25109415, 25296721, 28646536, 33349102). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 631809). 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000778542	SCV004032278	uncertain significance	Cystinuria	2023-08-02	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2_SUP,PP3
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000778542	SCV005398081	pathogenic	Cystinuria	2023-07-17	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 result in 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) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.01 (17 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated amino acid permease domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as homozygous, compound heterozygous, and as a single heterozygous variant in multiple individuals with cystinuria (PMIDs: 33349102, 25296721, 25964309). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomics England Pilot Project, Genomics England	RCV000778542	SCV001760445	pathogenic	Cystinuria		no assertion criteria provided	clinical testing