ClinVar Miner

Submissions for variant NM_004252.5(SLC9A3R1):c.458G>A (p.Arg153Gln) (rs41282065)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484640 SCV000565580 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing The R153Q variant in the SLC9A3R1 gene has been reported previously in the heterozygous state in a patient with hypophosphatemia and recurrent nephrolithiasis. Although family studies demonstrated R153Q segregated with disease in this family, no other genes related to the symptoms were evaluated (Karim et al., 2008). The R153Q variant was also found by whole exome sequencing in an individual and her son, who were both affected by hypophosphatemic rickets, but did not have nephrolithiasis (Brownstein et al., 2014). The NHLBI Exome Sequencing Project reports R153Q was observed in 39/8600 alleles (0.45%) from individuals of European ancestry. The R153Q variant was also observed on 205/66432 alleles (0.31%) from individuals of non-Finnish European background, including two unrelated homozygous individuals in the Exome Aggregation Consortium (ExAC) data set, indicating it may be a rare benign variant in this population. The R153Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function and in vitro expression studies showed that this variant impairs both the assembly and disassembly of the SLC9A3R1-related tenary complex, thus inhibiting phosphate transport, and cAMP accumulation was significantly higher in the cells transfected with the R153Q variant (Karim et al., 2008; Wang et al., 2012). However, similar results were found when likely benign SLC9A3R1 variants were tested (Karim et al., 2008; Wang et al., 2012). Based on review of the data in the context of the 2015 ACMG Standards and Guidelines for the Interpretation of Sequence Variants (Richards et al., 2015), R153Q in the SLC9A3R1 gene is now interpreted as a variant of uncertain significance
Fulgent Genetics,Fulgent Genetics RCV000005589 SCV000896666 uncertain significance Nephrolithiasis/osteoporosis, hypophosphatemic, 2 2018-10-31 criteria provided, single submitter clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland RCV001171340 SCV001328287 uncertain significance Chronic kidney disease 2020-05-28 criteria provided, single submitter research PP3, PP5
Invitae RCV000484640 SCV001642793 likely benign not provided 2020-12-04 criteria provided, single submitter clinical testing
OMIM RCV000005589 SCV000025771 pathogenic Nephrolithiasis/osteoporosis, hypophosphatemic, 2 2008-09-11 no assertion criteria provided literature only

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