ClinVar Miner

Submissions for variant NM_003052.5(SLC34A1):c.1223T>A (p.Val408Glu)

gnomAD frequency: 0.00011  dbSNP: rs140649226
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001370842 SCV001567385 pathogenic not provided 2025-01-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 408 of the SLC34A1 protein (p.Val408Glu). This variant is present in population databases (rs140649226, gnomAD 0.02%). This missense change has been observed in individual(s) with infantile hypercalcemia and/or kidney disease (PMID: 26047794, 31672324; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1061290). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC34A1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SLC34A1 function (PMID: 26047794). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001370842 SCV001777647 uncertain significance not provided 2021-04-23 criteria provided, single submitter clinical testing Published functional studies suggest V408E causes a loss of phosphate transport activity (Schlingmann et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31188746, 31672324, 29275531, 26047794)
CeGaT Center for Human Genetics Tuebingen RCV001370842 SCV003917016 likely pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing SLC34A1: PM3:Strong, PM2, PS3:Supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001370842 SCV004564029 uncertain significance not provided 2023-06-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV003983880 SCV005368075 likely pathogenic Hypercalcemia, infantile, 2 2024-04-08 criteria provided, single submitter clinical testing Criteria applied: PS3_MOD,PM3,PM5_SUP,PP3
Fulgent Genetics, Fulgent Genetics RCV005040226 SCV005671556 likely pathogenic Hypophosphatemic nephrolithiasis/osteoporosis 1; Fanconi renotubular syndrome 2; Hypercalcemia, infantile, 2 2024-04-17 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory, Biobizkaia Health Research Institute RCV003983880 SCV004708194 pathogenic Hypercalcemia, infantile, 2 2024-03-08 no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004734151 SCV005361241 pathogenic SLC34A1-related disorder 2024-05-30 no assertion criteria provided clinical testing The SLC34A1 c.1223T>A variant is predicted to result in the amino acid substitution p.Val408Glu. This variant was reported in the compound heterozygous state in an individual with idiopathic infantile hypercalcemia (Schlingmann et al. 2016. PubMed ID: 26047794). This variant was also reported in the heterozygous state in an individual with renal hypophosphatemia (Table S1, Hureaux et al. 2019. PubMed ID: 31672324). Functional studies showed that this variant causes reduced SLC34A1 trafficking to the plasma membrane and loss of phosphate transport activity (Schlingmann et al. 2016. PubMed ID: 26047794). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. A different nucleotide substitution affecting the same amino acid (p.Val408Met) is associated with renal hypophosphatemia (Table S1, Hureaux et al. 2019. PubMed ID: 31672324). Taken together, the c.1223T>A (p.Val408Glu) is interpreted as pathogenic.

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