rs121908891
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003060.4(SLC22A5):c.1196G>A(p.Arg399Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R399W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003060.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.1196G>A | p.Arg399Gln | missense_variant | 7/10 | ENST00000245407.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.1196G>A | p.Arg399Gln | missense_variant | 7/10 | 1 | NM_003060.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251466Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135908
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461888Hom.: 1 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74320
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2019 | Variant summary: SLC22A5 c.1196G>A (p.Arg399Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1196G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Wang_2001). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein resulted in markedly reduced carnitine transport compared to the wild-type OCTN2 (5%; Frigeni_2017, Wang_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). This variant is present in population databases (rs121908891, gnomAD 0.007%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6424). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 11715001). This variant disrupts the p.Arg399 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20027113, 20574985, 25132046, 28841266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2020 | Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28841266, 28711408, 11715001, 16652335, 27931018, 15714519, 28186590) - |
Decreased circulating carnitine concentration Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 05, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at