Submissions for variant NM_003052.5(SLC34A1):c.644G>A (p.Arg215Gln)

gnomAD frequency: 0.00005  dbSNP: rs1163121743

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001156016	SCV001317488	likely benign	Hypophosphatemic nephrolithiasis/osteoporosis 1	2018-01-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032436	SCV002239266	uncertain significance	not provided	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 215 of the SLC34A1 protein (p.Arg215Gln). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with infantile hypercalcemia (PMID: 27378183). ClinVar contains an entry for this variant (Variation ID: 906677). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SLC34A1 function (PMID: 27378183). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 27378183). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV002032436	SCV005325778	likely pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate this variant significantly reduced phosphate uptake and increased intracellular cytoplasmic accumulation of renal sodium phosphate cotransporter, NaPiIIa (Dinour et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27378183)
Neuberg Centre For Genomic Medicine, NCGM	RCV004726905	SCV005329533	likely pathogenic	Hypercalcemia, infantile, 2	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.644G>A (p.Arg215Gln) in the splice region in SLC34A1 gene has been reported in homozygousstate in an individual affected with infantile hypercalcemia (Dinour et. al. 2016). Experimental evidence shows conflicting evidencefor this variant with a partial retention of the mutant protein, significantly reduced sodium-dependent phosphate uptake butalmost similar electrogenic behavior as compared to the wild-type (Dinour et. al. 2016). The p.Arg215Gln variant is present with anallele frequency of 0.003% in gnomAD database. This variant has been submitted to the ClinVar database as Likely benign /Uncertain Significance. Computational evidence (SIFT - damaging; MutationTaster - disease causing) predict a damaging effecton protein structure and function for this variant. The amino acid change p.Arg215Gln in SLC34A1 is predicted as conserved byGERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 215 is changed to a Gln changing protein sequence andit might alter its composition and physico-chemical properties. This variant is present in the last position of exon 6 and splice AIpredicts a donor loss of 0.69 for this variant. Another missense variant [c.644G>A (p.Arg215Trp)] on the same position haspreviously been reported in homozygous state in an affected individual (Schlingmann et al. 2016), suggesting that this residuemight be of clinical significance. Additional literature and functional evidence will be required to prove the pathogenicity of thisvariant. . For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant inSLC34A1 gene, the molecular diagnosis is not confirmed.