ClinVar Miner

Submissions for variant NM_177550.5(SLC13A5):c.1280C>T (p.Ser427Leu)

gnomAD frequency: 0.00001  dbSNP: rs548065551
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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 RCV000202396 SCV001220173 pathogenic Developmental and epileptic encephalopathy, 25 2023-08-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 427 of the SLC13A5 protein (p.Ser427Leu). This variant is present in population databases (rs548065551, gnomAD no frequency). This missense change has been observed in individuals with clinical features of epileptic encephalopathy (PMID: 26384929, 27913086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218170). 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC13A5 protein function.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000202396 SCV001999881 likely pathogenic Developmental and epileptic encephalopathy, 25 2021-11-02 criteria provided, single submitter curation The p.Ser427Leu variant in SLC13A5 has been reported in 9 individuals with developmental and epileptic encephalopathy (PMID: 27913086, 26384929, 33063863, 27652284), segregated with disease in 3 affected relatives from 3 families (PMID: 27913086, 26384929), and has been identified in in 0.0009% (1/110,052) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs548065551). 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#: 218170) and has been interpreted as pathogenic by OMIM and Invitae. Of the 9 affected individuals, 2 were homozygotes, 2 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Ser427Leu variant is pathogenic (VariationID: 140753, 140752; PMID: 27913086, 27652284, 33063863). In vitro functional studies provide some evidence that the p.Ser427Leu variant may slightly impact protein function (PMID: 26384929). 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. 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: PM2_supporting, PM3, PP1_strong, PS3_supporting (Richards 2015).
PreventionGenetics, part of Exact Sciences RCV003955216 SCV004782175 likely pathogenic SLC13A5-related disorder 2024-02-15 criteria provided, single submitter clinical testing The SLC13A5 c.1280C>T variant is predicted to result in the amino acid substitution p.Ser427Leu. This variant was reported in the homozygous or compound heterozygous state in several families with epileptic encephalopathy or neonatal seizures (Weeke et al. 2017. PubMed ID: 27913086; Hardies et al. 2015. PubMed ID: 26384929). Functional studies showed that p.Ser427Leu substitution leads to a loss of citrate uptake due to a loss-of-function mechanism. Taken together, we classify this variant as likely pathogenic.
OMIM RCV000202396 SCV000257427 pathogenic Developmental and epileptic encephalopathy, 25 2015-11-01 no assertion criteria provided literature only

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