Submissions for variant NM_001177316.2(SLC34A3):c.1247del (p.Leu416fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003388712	SCV004100440	likely pathogenic	Autosomal recessive hypophosphatemic bone disease		criteria provided, single submitter	clinical testing	The frameshift deletion p.L416Pfs*65 in SLC34A3 (NM_001177316.2) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.L416Pfs*65 variant is observed in 8/30,598 (0.0261%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecuar diagnosis is not confirmed.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003669404	SCV004384736	pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu416Profs*65) in the SLC34A3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the SLC34A3 protein. This variant is present in population databases (rs781602446, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with urinary stone disease (PMID: 34805638). ClinVar contains an entry for this variant (Variation ID: 2627449). 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.