ClinVar Miner

Submissions for variant NM_177550.5(SLC13A5):c.1022G>A (p.Trp341Ter)

gnomAD frequency: 0.00001  dbSNP: rs150203483
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000202400 SCV000826829 pathogenic Developmental and epileptic encephalopathy, 25 2022-01-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp341*) in the SLC13A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC13A5 are known to be pathogenic (PMID: 24995870, 26384929). This variant is present in population databases (rs150203483, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 26384929). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218171). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV001549634 SCV001769818 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect (Hardies et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27261973, 26384929, 32551328, 24995870, 33063863)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000202400 SCV001999882 likely pathogenic Developmental and epileptic encephalopathy, 25 2021-11-02 criteria provided, single submitter curation The p.Trp341Ter variant in SLC13A5 has been reported in 3 individuals with developmental and epileptic encephalopathy (PMID: 26384929, 32551328), segregated with disease in 1 affected relative from 1 family (PMID: 26384929), and has been identified in 0.004% (5/1134840) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs150203483). 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. Of the 2 affected probands, 1 was a compound heterozygote that carried a variant of uncertain significance in trans which increases the likelihood that the p.Trp341Ter variant is pathogenic (Variation ID: 140752; PMID: 32551328, 26384929) This variant has also been reported in ClinVar (Variation ID#: 218171) and has been interpreted as pathogenic by Invitae and OMIM. In vitro functional studies provide some evidence that the p.Trp341Ter variant may slightly impact protein function (PMID: 26384929). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 341, which is predicted to lead to a truncated or absent protein. Loss of function of the SLC13A5 gene is strongly associated to autosomal recessive developmental and epileptic encephalopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive developmental and epileptic encephalopathy. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting, PM3_supporting, PS3_supporting (Richards 2015).
Genome-Nilou Lab RCV000202400 SCV002055649 pathogenic Developmental and epileptic encephalopathy, 25 2021-07-15 criteria provided, single submitter clinical testing
OMIM RCV000202400 SCV000257428 pathogenic Developmental and epileptic encephalopathy, 25 2015-11-01 no assertion criteria provided literature only

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