ClinVar Miner

Submissions for variant NM_177550.5(SLC13A5):c.425C>T (p.Thr142Met)

gnomAD frequency: 0.00001  dbSNP: rs761917087
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000202397 SCV000826730 pathogenic Developmental and epileptic encephalopathy, 25 2024-04-15 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 142 of the SLC13A5 protein (p.Thr142Met). This variant is present in population databases (rs761917087, gnomAD 0.003%). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy and amelogenesis imperfecta and SLC13A5-related conditions (PMID: 26384929, 27600704; Invitae). 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: 218173). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC13A5 protein function. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000202397 SCV001430127 pathogenic Developmental and epileptic encephalopathy, 25 2019-06-11 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000202397 SCV001999889 likely pathogenic Developmental and epileptic encephalopathy, 25 2021-11-02 criteria provided, single submitter curation The p.Thr142Met variant in SLC13A5 has been reported in 9 individuals across 5 families (PMID: 26384929, 32551328, 33063863, 29138412), and has been identified in in 0.003% (1/30574) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761917087). 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 5 families, one had 3 compound heterozygous relatives that carried reported pathogenic variants in trans, two had 2 homozygous relatives, and two had 2 compound heterozygotes that carried a variant of uncertain significance in trans, which increases the likelihood that the p.Thr227Met variant is pathogenic (PMID: 26384929, 32551328, 33063863, 29138412). This variant has also been reported in ClinVar (Variation ID#: 218173) and has been interpreted as likely pathogenic by Invitae and pathogenic by OMIM and Institute of Human Genetics (Klinikum rechts der Isar). In vitro functional studies provide some evidence that the p.Thr142Met variant may slightly impact protein function (PMID: 26384929, 33040525). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Thr142Met variant is located in a region of SLC13A5 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 33040525). 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, 25. ACMG/AMP Criteria applied: PM2_supporting, PM3, PP1_strong, PS3_supporting, PM1_supporting (Richards 2015).
Genome-Nilou Lab RCV000202397 SCV002055652 likely pathogenic Developmental and epileptic encephalopathy, 25 2021-07-15 criteria provided, single submitter clinical testing
GeneDx RCV003226911 SCV003923554 pathogenic not provided 2024-07-29 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: T142M abolishes transporter function (PMID: 26384929); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27600704, 32551328, 33063863, 31440721, 26384929, 37025451)
Suma Genomics RCV000202397 SCV005687488 likely pathogenic Developmental and epileptic encephalopathy, 25 criteria provided, single submitter clinical testing A missense variant c.425C>T, p.(Thr142Met) is observed in exon 4 of SLC13A5 in homozygous state. This variant is observed in 19 individuals in the gnomAD database in heterozygous state. ACMG criteria met: PS3_Supporting, PM2_Supporting, and PM3_Very strong
OMIM RCV000202397 SCV000257430 pathogenic Developmental and epileptic encephalopathy, 25 2015-11-01 no assertion criteria provided literature only

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