ClinVar Genomic variation as it relates to human health
NM_177550.5(SLC13A5):c.655G>A (p.Gly219Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_177550.5(SLC13A5):c.655G>A (p.Gly219Arg)
Variation ID: 140752 Accession: VCV000140752.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 6703031 (GRCh38) [ NCBI UCSC ] 17: 6606350 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2015 Apr 15, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_177550.5:c.655G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_808218.1:p.Gly219Arg missense NM_001143838.3:c.655G>A NP_001137310.1:p.Gly219Arg missense NM_001284509.2:c.604G>A NP_001271438.1:p.Gly202Arg missense NM_001284510.2:c.526G>A NP_001271439.1:p.Gly176Arg missense NC_000017.11:g.6703031C>T NC_000017.10:g.6606350C>T NG_034220.1:g.15391G>A LRG_1020:g.15391G>A LRG_1020t1:c.655G>A LRG_1020p1:p.Gly219Arg - Protein change
- G219R, G176R, G202R
- Other names
- SLC13A5, GLY219ARG (rs144332569)
- NM_177550.4(SLC13A5):c.655G>A
- p.Gly219Arg
- Canonical SPDI
- NC_000017.11:6703030:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00012
The Genome Aggregation Database (gnomAD), exomes 0.00016
Exome Aggregation Consortium (ExAC) 0.00021
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC13A5 | - | - |
GRCh38 GRCh37 |
715 | 739 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (12) |
criteria provided, multiple submitters, no conflicts
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Jan 27, 2024 | RCV000128860.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 1, 2020 | RCV001311105.16 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 23, 2017 | RCV002362772.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140224.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
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Pathogenic
(Jun 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430126.1
First in ClinVar: Aug 20, 2020 Last updated: Aug 20, 2020 |
Sex: female
Tissue: blood
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Likely pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002055651.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
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Pathogenic
(Nov 02, 2021)
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criteria provided, single submitter
Method: curation
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Developmental and epileptic encephalopathy, 25
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001999886.2
First in ClinVar: Nov 05, 2021 Last updated: Feb 02, 2022 |
Comment:
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), … (more)
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). (less)
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Pathogenic
(Jan 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV000992831.2
First in ClinVar: Aug 26, 2019 Last updated: Oct 06, 2023 |
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000655338.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Aug 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501150.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894146.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jan 01, 2014)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: yes
Allele origin:
inherited
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000965826.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
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Likely pathogenic
(Jun 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002665265.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: research
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Developmental and epileptic encephalopathy, 25
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, University of Torino
Study: NeuroWES
Accession: SCV002760167.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(Sep 26, 2019)
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no assertion criteria provided
Method: clinical testing
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Developmental and epileptic encephalopathy, 25
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133192.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(Nov 01, 2015)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 25 WITH AMELOGENESIS IMPERFECTA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000172714.5
First in ClinVar: Aug 06, 2014 Last updated: Oct 10, 2021 |
Comment on evidence:
In a brother and sister with developmental and epileptic encephalopathy-25 with amelogenesis imperfecta (DEE25; 615905), Thevenon et al. (2014) identified compound heterozygous mutations in the … (more)
In a brother and sister with developmental and epileptic encephalopathy-25 with amelogenesis imperfecta (DEE25; 615905), Thevenon et al. (2014) identified compound heterozygous mutations in the SLC13A5 gene: a c.655G-A transition, resulting in a gly219-to-arg (G219R) substitution, and a c.680C-T transition, resulting in a thr227-to-met (T227M; 608305.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by capillary sequencing, segregated with the disorder in the family. The mutations were filtered against the dbSNP (build 138) database, and neither was found in the Exome Variant Server database or in 50 local exomes of unaffected individuals. The G219R mutation was present in dbSNP (build 134) as rs144332569 without frequency or validation data. Both mutations affected highly conserved residues in the Na1 sodium-binding domain, which is required for citrate transport. Thevenon et al. (2014) postulated that the mutations affected the ability of SLC13A5 to transport citrate across the plasma membrane, but functional studies were not performed. An unrelated boy with a similar phenotype was found to carry the same compound heterozygous mutations. SNP analysis argued against identity by descent, supporting distinct mutational events in these 2 families. This latter patient was ascertained from a cohort of 68 additional probands with early-onset epilepsy who were screened for SLC13A5 mutations. The patients had onset of seizures in the first days of life. In 3 German sibs (family C) with DEE25, Hardies et al. (2015) identified compound heterozygous mutations in the SLC13A5 gene: G219R and a c.425C-T transition resulting in a thr142-to-met (T142M; 608305.0007) substitution at a highly conserved residue near the first sodium binding site. Hardies et al. (2015) stated that the G219R substitution occurred at a highly conserved residue in transmembrane domain 5a. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations were found at a low frequency in the ExAC database (0.041% for G219R and 0.002% for T142M). In vitro functional expression studies in HEK293T cells showed that the G219R mutant protein was retained intracellularly at the endoplasmic reticulum and was not expressed at the cell membrane, whereas the T142M mutant protein was expressed normally at the cell membrane. However, both mutant proteins lost functional citrate transport activity. The patients had onset of seizures in the first days of life. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Developmental and epileptic encephalopathy, 25
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000494179.1
First in ClinVar: Dec 06, 2015 Last updated: Dec 06, 2015 |
Comment:
This variant was identified as compound heterozygous in an individual with epileptic encephalopathy.
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Lessons learned from additional research analyses of unsolved clinical exome cases. | Eldomery MK | Genome medicine | 2017 | PMID: 28327206 |
Punctate white matter lesions in full-term infants with neonatal seizures associated with SLC13A5 mutations. | Weeke LC | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2017 | PMID: 27913086 |
Disease Heterogeneity in Na(+)/Citrate Cotransporter Deficiency. | Anselm I | JIMD reports | 2017 | PMID: 26960556 |
Mutations in the Na(+)/citrate cotransporter NaCT (SLC13A5) in pediatric patients with epilepsy and developmental delay. | Klotz J | Molecular medicine (Cambridge, Mass.) | 2016 | PMID: 27261973 |
Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia. | Hardies K | Brain : a journal of neurology | 2015 | PMID: 26384929 |
Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life. | Thevenon J | American journal of human genetics | 2014 | PMID: 24995870 |
Text-mined citations for rs144332569 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.