Submissions for variant NM_177550.5(SLC13A5):c.655G>A (p.Gly219Arg)

gnomAD frequency: 0.00009  dbSNP: rs144332569

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000128860	SCV000655338	pathogenic	Developmental and epileptic encephalopathy, 25	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 219 of the SLC13A5 protein (p.Gly219Arg). This variant is present in population databases (rs144332569, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive epileptic encephalopathy (PMID: 24995870, 26384929, 26960556, 27261973). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 140752). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC13A5 function (PMID: 26384929, 27261973). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000128860	SCV000894146	likely pathogenic	Developmental and epileptic encephalopathy, 25	2018-10-31	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000128860	SCV000965826	pathogenic	Developmental and epileptic encephalopathy, 25	2014-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000128860	SCV000992831	pathogenic	Developmental and epileptic encephalopathy, 25	2023-01-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000128860	SCV001140224	pathogenic	Developmental and epileptic encephalopathy, 25	2019-05-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000128860	SCV001430126	pathogenic	Developmental and epileptic encephalopathy, 25	2019-06-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311105	SCV001501150	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000128860	SCV001999886	pathogenic	Developmental and epileptic encephalopathy, 25	2021-11-02	criteria provided, single submitter	curation	The p.Gly219Arg variant in SLC13A5 has been reported in many individuals with developmental and epileptic encephalopathy (PMID: 26384929, 24995870, 27261973, 27913086, 31216405, 32551328, TESS cohort), segregated with disease in 8 affected relatives from 7 families (PMID: 26384929, 24995870, 27261973, 27913086, TESS cohort), and has been identified in 0.03% (31/113680) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs144332569). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of the affected individuals, 2 were homozygotes and 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly219Arg variant is pathogenic (VariationID: 218173, PMID: 26384929, 27261973, 27913086). This variant has also been reported in ClinVar (Variation ID#: 140752) and has been interpreted as likely pathogenic or pathogenic by multiple submitters. In vitro functional studies provide some evidence that the p.Gly219Arg variant may impact protein function (PMID: 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive developmental and epileptic encephalopathy. ACMG/AMP Criteria applied: PP1_strong, PM3_strong, PP3, PS3_moderate (Richards 2015).
Genome-Nilou Lab	RCV000128860	SCV002055651	likely pathogenic	Developmental and epileptic encephalopathy, 25	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362772	SCV002665265	likely pathogenic	Inborn genetic diseases	2017-06-23	criteria provided, single submitter	clinical testing	The p.G219R variant (also known as c.655G>A), located in coding exon 5 of the SLC13A5 gene, results from a G to A substitution at nucleotide position 655. The glycine at codon 219 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in homozygotes and compound heterozygotes with autosomal recessive early infantile epileptic encephalopathy (Thevenon J et al. Am. J. Hum. Genet., 2014 Jul;95:113-20; Klotz J et al. Mol. Med., 2016 May;22:310-321; Anselm I et al. JIMD Rep, 2017 Mar;31:107-111; Eldomery MK et al. Genome Med, 2017 Mar;9:26; Weeke LC et al. Eur. J. Paediatr. Neurol., 2017 Mar;21:396-403). Functional studies suggest that this alteration affects the transport activities of the protein (Klotz J et al. Mol. Med., 2016 May;22:310-321). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory of Medical Genetics, University of Torino	RCV000128860	SCV002760167	pathogenic	Developmental and epileptic encephalopathy, 25	2022-11-29	criteria provided, single submitter	research
OMIM	RCV000128860	SCV000172714	pathogenic	Developmental and epileptic encephalopathy, 25	2015-11-01	no assertion criteria provided	literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000128860	SCV000494179	pathogenic	Developmental and epileptic encephalopathy, 25		no assertion criteria provided	research	This variant was identified as compound heterozygous in an individual with epileptic encephalopathy.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000128860	SCV001133192	pathogenic	Developmental and epileptic encephalopathy, 25	2019-09-26	no assertion criteria provided	clinical testing