rs386134221
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4
The NM_003060.4(SLC22A5):c.1403C>A(p.Thr468Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T468R) has been classified as Pathogenic.
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.1403C>A | p.Thr468Lys | missense_variant | 8/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.1403C>A | p.Thr468Lys | missense_variant | 8/10 | 1 | NM_003060.4 | ENSP00000245407 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251472Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135910
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 468 of the SLC22A5 protein (p.Thr468Lys). This variant is present in population databases (rs386134221, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SLC22A5-related conditions. ClinVar contains an entry for this variant (Variation ID: 529852). 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 SLC22A5 protein function. This variant disrupts the p.Thr468 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12210323, 15714519, 16652335). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Decreased circulating carnitine concentration Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 19, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at