ClinVar Genomic variation as it relates to human health

The c.1511delT variant in the SLC13A5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.1511delT variant causes a frameshift that is predicted to result in protein truncation, as the last 65 amino acids are lost and replaced with 22 incorrect amino acids; however, loss-of-function variants have not been published downstream of this position in the protein. The c.1511delT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1511delT as a likely pathogenic variant.

The c.1438-1255del variant in SLC13A5 has been reported in 2 individuals with developmental and epileptic encephalopathy (PMID: 31780880, TESS cohort) and has been identified in 0.01% (1/8712) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1211773372). 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 2 affected individuals, 1 of those was a homozygote and 1 was a compound heterozygote that carried a variant of uncertain significance in trans, which increases the likelihood that the c.1438-1255del variant is pathogenic (VariationID: 842942; PMID: 31780880, TESS Cohort). This variant has also been reported in ClinVar (Variation ID#: 449231) and has been interpreted as VUS by Invitae and likely pathogenic by GeneDx. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 504 and leads to a premature termination codon 23 amino acids downstream. This termination codon occurs (within the terminal 50 bases of the second to last exon) and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the SLC13A5 gene is a strongly established disease mechanism in autosomal recessive developmental and epileptic encephalopathy, 25. In summary, the clinical significance of the c.1438-1255del variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PVS1_supporting (Richards 2015).

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Leu504Cysfs*23) in the SLC13A5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 65 amino acid(s) of the SLC13A5 protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with SLC13A5-related conditions (PMID: 31780880). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 449231). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the SLC13A5 protein in which other variant(s) (p.Pro505Leu) have been determined to be pathogenic (PMID: 31780880, 33258288; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

The c.1511delT (p.L504Cfs*23) alteration, located in coding exon 11 of the SLC13A5 gene, consists of a deletion of one nucleotide at position 1511, causing a translational frameshift with a predicted alternate stop codon after 23 amino acids. This alteration occurs at the 3' terminus of the SLC13A5 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 42 amino acids of the protein. The exact functional effect of this alteration is unknown. This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was seen in trans along with another SLC13A5 variant, c.1514C>T (p.P505L), in a child with neonatal refractory epilepsy, epileptic/infantile spasms, abnormal brain wave patterns, intellectual disability, and severe psychomotor development delay (Fernández-Marmiesse, 2019). This variant has also been reported as a homozygous finding in a child with a diagnosis of SLC13A5 citrate transporter disorder (Spelbrink, 2023). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.