Submissions for variant NM_003052.5(SLC34A1):c.458G>T (p.Gly153Val)

dbSNP: rs769409705

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778761	SCV000915126	likely pathogenic	SLC34A1-related disorder	2018-11-27	criteria provided, single submitter	clinical testing	The SLC34A1 c.458G>T (p.Gly153Val) missense variant has been reported in two studies and is found in a total of three individuals affected with either idiopathic infantile hypercalcemia or hypophosphatemia (Schlingmann et al. 2016; Braun et al. 2016). The three affected individuals include each in a homozygous, compound heterozygous, and heterozygous state. The p.Gly153Val variant was absent from 204 controls and is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Genome Aggregation Database. Functional analysis in Xenopus oocytes showed that wildtype protein induced significant uptake of labeled phosphate, whereas the p.Gly153Val variant did not induce uptake significantly different from that of noninjected control cells. Transiently transfected opossum kidney cells showed complete intracellular retention of mutant protein with no detectable actin colocalization, in contrast to the wild type protein, which localized at the plasma membrane and colocalized with actin (Schlingmann et al. 2016). Based on the collective evidence, the p.Gly153Val variant is classified as likely pathogenic for SLC34A1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV002500742	SCV002807050	likely pathogenic	Hypophosphatemic nephrolithiasis/osteoporosis 1; Fanconi renotubular syndrome 2; Hypercalcemia, infantile, 2	2021-08-05	criteria provided, single submitter	clinical testing
GeneDx	RCV003233505	SCV003931018	likely pathogenic	not provided	2022-12-07	criteria provided, single submitter	clinical testing	Published functional studies demonstrate G153V results in loss of function compared to wildtype (Schlingmann 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: 31589614, 26787776, 31188746, 33326653, 26047794)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003233505	SCV004293235	likely pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 153 of the SLC34A1 protein (p.Gly153Val). This variant is present in population databases (rs769409705, gnomAD 0.004%). This missense change has been observed in individuals with infantile hypercalcemia (PMID: 26047794). ClinVar contains an entry for this variant (Variation ID: 234927). 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 expected to disrupt SLC34A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC34A1 function (PMID: 26047794). This variant disrupts the p.Gly153 amino acid residue in SLC34A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26047794). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000223664	SCV004806985	likely pathogenic	Hypercalcemia, infantile, 2	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000223664	SCV000280016	pathogenic	Hypercalcemia, infantile, 2	2016-10-06	no assertion criteria provided	literature only