ClinVar Miner

Submissions for variant NM_001177316.2(SLC34A3):c.1248_1249del (p.Leu417fs)

dbSNP: rs757714479
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001227960 SCV001400340 pathogenic not provided 2022-08-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu417Thrfs*175) in the SLC34A3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the SLC34A3 protein. This variant is present in population databases (rs757714479, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with renal hypophosphatemia although a second variant was not observed (PMID: 31672324). ClinVar contains an entry for this variant (Variation ID: 955341). 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 RCV002290646 SCV002579692 likely pathogenic Autosomal recessive hypophosphatemic bone disease 2022-02-08 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002290646 SCV002792254 likely pathogenic Autosomal recessive hypophosphatemic bone disease 2022-03-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004746281 SCV005344466 pathogenic SLC34A3-related disorder 2024-03-12 no assertion criteria provided clinical testing The SLC34A3 c.1248_1249delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu417Thrfs*175). This frameshift variant is predicted to result in a premature termination at amino acid #592, which is 8 amino acids proximal to the end of the wild-type protein. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the C-terminal region of the SLC34A3 protein; such variants have been reported in trans with another pathogenic variant in individuals with SLC34A3-related disorders (for example see: p.Arg547Alafs*41, ClinVarID: 444096; Ser435Thrfs*46, Ichikawa et al. 2014. PubMed ID: 24176905). This variant was identified in the homozygous state in a patient with an SLC34A3-associated disorder (Internal Data, PreventionGenetics) and in a heterozygous state in two individuals with renal hypophosphataemia or suspected primary hyperoxaluria (Hureaux et al 2019. PubMed ID: 31672324; also known as c.1246_1247del (p.Leu417Thrfs) in Cogal et al. 2021. PubMed ID: 34805638). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

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