Submissions for variant NM_001177316.2(SLC34A3):c.1304del (p.Ser435fs)

gnomAD frequency: 0.00019  dbSNP: rs771816857

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386143	SCV001586275	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser435Thrfs*46) in the SLC34A3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acid(s) of the SLC34A3 protein. This variant is present in population databases (rs771816857, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 24176905). ClinVar contains an entry for this variant (Variation ID: 1031579). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the SLC34A3 protein in which other variant(s) (p.Trp541*) have been determined to be pathogenic (PMID: 31440709). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV001780253	SCV002579703	likely pathogenic	Autosomal recessive hypophosphatemic bone disease	2022-02-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001780253	SCV002811667	pathogenic	Autosomal recessive hypophosphatemic bone disease	2022-02-03	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001386143	SCV005198272	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001780253	SCV005627526	likely pathogenic	Autosomal recessive hypophosphatemic bone disease	2024-12-17	criteria provided, single submitter	clinical testing	Criteria applied: PVS1_STR,PM2_SUP,PM3_SUP
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001780253	SCV005914987	likely pathogenic	Autosomal recessive hypophosphatemic bone disease	2022-09-15	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV004746328	SCV005361653	pathogenic	SLC34A3-related disorder	2024-04-18	no assertion criteria provided	clinical testing	The SLC34A3 c.1304delG variant is predicted to result in a frameshift and premature protein termination (p.Ser435Thrfs*46). This variant has been reported in the compound heterozygous state in a patient with nephrolithiasis and increased urinary excretion of calcium without bone deformity or history of fractures (Ichikawa et al. 2014. PubMed ID: 24176905). This variant is reported in 0.082% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in SLC34A3 are expected to be pathogenic. Given the evidence, we interpret c.1304del (p.Ser435Thrfs*46) as pathogenic.