ClinVar Miner

Submissions for variant NM_177550.5(SLC13A5):c.1460C>T (p.Pro487Leu)

gnomAD frequency: 0.00001  dbSNP: rs779336736
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001201857 SCV001372948 uncertain significance Developmental and epileptic encephalopathy, 25 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 487 of the SLC13A5 protein (p.Pro487Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of SLC13A5-related conditions (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 933613). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001201857 SCV001999893 uncertain significance Developmental and epileptic encephalopathy, 25 2021-11-02 criteria provided, single submitter curation The p.Pro487Leu variant in SLC13A5 has been reported in 1 individual with developmental and epileptic encephalopathy (TESS Cohort) and has been identified in 0.002% (3/127212) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779336736). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 933613) and has been interpreted as VUS by Invitae. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro487Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting (Richards 2015).
GeneDx RCV004726948 SCV005332773 uncertain significance not provided 2023-09-27 criteria provided, single submitter clinical testing Reported with a second variant in the SLC13A5 gene in a patient with epilepsy and global developmental delay in published literature; however, segregation information was not provided (Spellbrink et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); 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: 35217970, 34822404, 37025451)

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