rs201262157

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003060.4(SLC22A5):ā€‹c.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

Scores

8
9
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.22
Variant links:
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
SLC22A5NM_003060.4 linkuse as main transcriptc.791C>G p.Thr264Arg missense_variant 4/10 ENST00000245407.8 NP_003051.1 O76082-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC22A5ENST00000245407.8 linkuse as main transcriptc.791C>G p.Thr264Arg missense_variant 4/101 NM_003060.4 ENSP00000245407.3 O76082-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251456
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461876
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152156
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingBaylor GeneticsNov 29, 2023- -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 07, 2022Variant 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 submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 31, 2024- -
Likely pathogenic, criteria provided, single submitterin vitro;researchGiacomini Lab, University of California, San FranciscoOct 03, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 06, 2023This 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 providedclinical testingPreventionGenetics, part of Exact SciencesJan 18, 2024The 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 submitterclinical testingGeneDxMar 20, 2019Published 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.79
D;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.081
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Pathogenic
3.7
H;.;.
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0080
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.90
MutPred
0.89
Gain of methylation at T264 (P = 0.0097);.;.;
MVP
0.93
MPC
0.83
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.96
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201262157; hg19: chr5-131721158; API