Submissions for variant NM_177550.5(SLC13A5):c.680C>T (p.Thr227Met)

gnomAD frequency: 0.00004  dbSNP: rs587777577

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000128861	SCV000655340	pathogenic	Developmental and epileptic encephalopathy, 25	2023-08-29	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, 27261973). 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. ClinVar contains an entry for this variant (Variation ID: 140753). This missense change has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 24995870, 26384929, 27261973, 27600704, 27913086, 28673551, 30525188, 32551328, 33063863). 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. This variant is present in population databases (rs587777577, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 227 of the SLC13A5 protein (p.Thr227Met).
Laboratory for Molecular Medicine, Mass General Brigham 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
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000128861	SCV001999885	likely pathogenic	Developmental and epileptic encephalopathy, 25	2021-11-02	criteria provided, single submitter	curation	The p.Thr227Met variant in SLC13A5 has been reported in at least 10 individuals with developmental and epileptic encephalopathy (PMID: 24995870, 26384929, 27261973, 27600704, 28673551, 27913086, 31231135, 32551328, 33063863), and has been identified in 0.004% (1/24960) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs140115503). 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 10 affected individuals, 3 of those were homozygotes and 5 were compound heterozygotes that carried reported pathogenic/likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the p.Thr227Met variant is pathogenic (Variation ID#: 140752, 280534; PMID: 24995870, 27261973, 27600704, 28673551, 31231135). This variant has also been reported in ClinVar (Variation ID#: 140753) and has been interpreted as VUS by Invitae, likely pathogenic by Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), and pathogenic by OMIM, Lupski Lab (Baylor-Hopkins CMG, Baylor College of Medicine), and Equipe Genetique des Anomalies du Developpement (Université de Bourgogne). In vitro functional studies provide some evidence that the p.Thr227Met variant may slightly impact protein function (PMID: 33040525, 26384929, 27261973). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Thr227Met 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: 26384929, 27261973). 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: PM3_strong, PM2_supporting, PP3, PS3_supporting, PM1_supporting (Richards 2015).
Genome-Nilou Lab	RCV000128861	SCV002055645	pathogenic	Developmental and epileptic encephalopathy, 25	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001701766	SCV005325078	pathogenic	not provided	2023-10-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27600704, 31231135, 32551328, 26384929, 27261973, 30054523, 33063863, 30525188, 28673551, 24995870, 27913086)
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000128861	SCV005873623	pathogenic	Developmental and epileptic encephalopathy, 25	2019-10-05	criteria provided, single submitter	clinical testing
OMIM	RCV000128861	SCV000172715	pathogenic	Developmental and epileptic encephalopathy, 25	2015-11-01	no assertion criteria provided	literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000128861	SCV000494181	pathogenic	Developmental and epileptic encephalopathy, 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	Developmental and epileptic encephalopathy, 25		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701766	SCV001932333	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001701766	SCV001957499	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001701766	SCV001967852	likely pathogenic	not provided		no assertion criteria provided	clinical testing