ClinVar Miner

Submissions for variant NM_177550.4(SLC13A5):c.680C>T (p.Thr227Met) (rs587777577)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000128861 SCV000655340 uncertain significance Epileptic encephalopathy, early infantile, 25 2017-04-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 227 of the SLC13A5 protein (p.Thr227Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs587777577, ExAC 0.009%). This variant has been reported to segregate with neonatal epileptic encephalopathy in several small families (PMID: 24995870, 26384929, 27261973). ClinVar contains an entry for this variant (Variation ID: 140753). Experimental studies have shown that this missense change disrupts SLC13A5 transporter activity, however the studies disagree as to the exact mechanism of this disruption (PMID: 26384929, 27261973). In summary, this variant is a rare missense change that disrupts protein function in cell culture. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826127 SCV000967638 likely pathogenic Undetermined early-onset epileptic encephalopathy 2018-03-23 criteria provided, single submitter clinical testing The p.Thr227Met variant in SLC13A5 has been reported in 4 individuals with epile ptic encephalopathy and segregated with the disease in 1 affected family member; 3 of these individuals were compound heterozygous for the variant and one of th em homozygous (Hardies 2015, Klotz 2016, Thevenon 2014). This variant has also b een reported in ClinVar (Variation ID# 140753). This variant has been identified in 0.002% (3/126,362) of European chromosomes by the Genome Aggregation Databas e (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587777577). Although this v ariant has been seen in the general population, its frequency is low enough to b e consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that the p.Thr227Met variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In vitro functional studies provide some evidence that the p.Thr227Met varia nt may impact protein function (Hardies 2015, Klotz 2016). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, t he p.Thr227Met variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3 _Strong, PS3_Supporting, PP3
OMIM RCV000128861 SCV000172715 pathogenic Epileptic encephalopathy, early infantile, 25 2015-11-01 no assertion criteria provided literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000128861 SCV000494181 pathogenic Epileptic encephalopathy, early infantile, 25 no assertion criteria provided research This variant was identified as compound heterozygous in an individual with epileptic encephalopathy.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000128861 SCV000965825 pathogenic Epileptic encephalopathy, early infantile, 25 no assertion criteria provided clinical testing

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