rs587777577
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_177550.5(SLC13A5):c.680C>T(p.Thr227Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T227T) 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 | UniProt |
---|---|---|---|---|---|---|---|
SLC13A5 | NM_177550.5 | c.680C>T | p.Thr227Met | missense_variant | 5/12 | ENST00000433363.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC13A5 | ENST00000433363.7 | c.680C>T | p.Thr227Met | missense_variant | 5/12 | 1 | NM_177550.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152262Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251128Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135748
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727226
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152262Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74388
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 25 Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
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, no assertion criteria provided | literature only | OMIM | Nov 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2023 | ClinVar contains an entry for this variant (Variation ID: 140753). 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). This variant is present in population databases (rs587777577, gnomAD 0.004%). 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. 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. 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 | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 02, 2021 | 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not provided Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Undetermined early-onset epileptic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 23, 2018 | 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 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at