rs144332569
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_177550.5(SLC13A5):c.655G>A(p.Gly219Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G219E) has been classified as Likely benign.
Frequency
Consequence
NM_177550.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC13A5 | NM_177550.5 | c.655G>A | p.Gly219Arg | missense_variant | 5/12 | ENST00000433363.7 | NP_808218.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC13A5 | ENST00000433363.7 | c.655G>A | p.Gly219Arg | missense_variant | 5/12 | 1 | NM_177550.5 | ENSP00000406220.2 |
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152238Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000155 AC: 39AN: 251354Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135872
GnomAD4 exome AF: 0.000191 AC: 279AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.000198 AC XY: 144AN XY: 727238
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152238Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74390
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 25 Pathogenic:12
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics, University of Torino | Nov 29, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 02, 2021 | 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). - |
Pathogenic, no assertion criteria provided | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | This variant was identified as compound heterozygous in an individual with epileptic encephalopathy. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 11, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2017 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at