rs201262157
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003060.4(SLC22A5):āc.791C>Gā(p.Thr264Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.000014 ( 0 hom. )
Consequence
SLC22A5
NM_003060.4 missense
NM_003060.4 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 7.22
Genes affected
SLC22A5 (HGNC:10969): (solute carrier family 22 member 5) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is a plasma integral membrane protein which functions both as an organic cation transporter and as a sodium-dependent high affinity carnitine transporter. The encoded protein is involved in the active cellular uptake of carnitine. Mutations in this gene are the cause of systemic primary carnitine deficiency (CDSP), an autosomal recessive disorder manifested early in life by hypoketotic hypoglycemia and acute metabolic decompensation, and later in life by skeletal myopathy or cardiomyopathy. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975
PP5
Variant 5-132385466-C-G is Pathogenic according to our data. Variant chr5-132385466-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 460416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.791C>G | p.Thr264Arg | missense_variant | 4/10 | ENST00000245407.8 | NP_003051.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.791C>G | p.Thr264Arg | missense_variant | 4/10 | 1 | NM_003060.4 | ENSP00000245407.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251456Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135904
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727236
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74308
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renal carnitine transport defect Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 29, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2022 | Variant summary: SLC22A5 c.791C>G (p.Thr264Arg) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251456 control chromosomes (gnomAD). c.791C>G has been reported in the literature as a biallelic genotype in at least two individuals affected with Systemic Primary Carnitine Deficiency, identified through newborn screening programs (e.g. Li_2010, Martin-Rivada_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Frigeni_2017). Carnitine transport activity was reduced to < 3% of normal in cells expressing the variant, suggesting it negatively impacts protein function. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Three classified the variant as likely pathogenic and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | in vitro;research | Giacomini Lab, University of California, San Francisco | Oct 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 264 of the SLC22A5 protein (p.Thr264Arg). This variant is present in population databases (rs201262157, gnomAD 0.008%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20574985, 35281663). ClinVar contains an entry for this variant (Variation ID: 460416). 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%. For these reasons, this variant has been classified as Pathogenic. - |
SLC22A5-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 18, 2024 | The SLC22A5 c.791C>G variant is predicted to result in the amino acid substitution p.Thr264Arg. This variant has been reported in the homozygous state in an individual with autosomal recessive carnitine deficiency (Li et al 2010. PubMed ID: 20574985). A functional assay indicates this variant results in ~2.5% enzyme activity in comparison to the wild-type protein (Frigeni M et al 2017. PubMed ID: 28841266). This variant was observed in a patient tested at PreventionGenetics with an additional pathogenic SLC22A5 variant and low carnitine levels (Internal Data). In summary, we categorize the c.791C>G variant as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2019 | Published functional studies demonstrate T264R is associated with significantly reduced carnitine transport (Frigeni et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20574985, 28841266) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of methylation at T264 (P = 0.0097);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at