5-132387044-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000245407.8(SLC22A5):​c.844C>T​(p.Arg282Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,972 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SLC22A5
ENST00000245407.8 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 2.31
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-132387044-C-T is Pathogenic according to our data. Variant chr5-132387044-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132387044-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC22A5NM_003060.4 linkuse as main transcriptc.844C>T p.Arg282Ter stop_gained 5/10 ENST00000245407.8 NP_003051.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC22A5ENST00000245407.8 linkuse as main transcriptc.844C>T p.Arg282Ter stop_gained 5/101 NM_003060.4 ENSP00000245407 P1O76082-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152140
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251492
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135918
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461832
Hom.:
0
Cov.:
32
AF XY:
0.0000619
AC XY:
45
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000656
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152140
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000137
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Renal carnitine transport defect Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017The SLC22A5 c.844C>T (p.Arg282Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg282Ter variant has been reported in at least seven studies in a total of ten individuals with systemic primary carnitine deficiency, including in three in a homozygous state, in three in a compound heterozygous state, and in four in a heterozygous state (Burwinkel et al. 1999; Wang et al. 1999; Vaz et al. 1999; Dobrowolski et al. 2005; Li et al. 2010; Kilic et al. 2012; Rose et al. 2012). The mother of one of the heterozygous patients was also a carrier of the variant but was asymptomatic. Control data are not available for the p.Arg282Ter variant, which is reported at a frequency of 0.00029 in the African population of the Exome Aggregation Consortium. The p.Arg282Ter variant has also been associated with an unconventional splicing defect (Burwinkel et al. 1999). Fibroblasts from one of the homozygous individuals were shown to exhibit absent saturable carnitine transport and 25% of the normal mRNA expression. Functional studies in Chinese hamster ovary cells showed that transfection with the wildtype protein could increase carnitine transport but that expression of the p.Arg282Ter variant protein could not (Wang et al. 1999). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg282Ter variant is classified as pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 19, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 02, 1999- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 21, 2021- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMay 22, 2020- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change creates a premature translational stop signal (p.Arg282*) in the SLC22A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A5 are known to be pathogenic (PMID: 9916797). This variant is present in population databases (rs121908886, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with primary carnitine deficiency (PMID: 10051646, 10425211, 10480371, 21922592). ClinVar contains an entry for this variant (Variation ID: 6416). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 27, 2018Variant summary: SLC22A5 c.844C>T (p.Arg282X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.9e-05 in 121404 control chromosomes (gnomAD). c.844C>T has been reported in the literature in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Wang 1999, Burwinkel 1999, Dobrowolski 2005, Rose 2012). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Wang 1999, Frigeni 2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 30, 2020Reported in patients with an abnormal newborn screen for primary carnitine deficiency who did not have a second variant described (Li et al., 2010); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23090741, 10051646, 25087612, 25525159, 15714519, 20574985, 12204000, 10480371, 29636919, 28841266, 23430869, 21922592, 10425211) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2019- -
SLC22A5-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 18, 2024The SLC22A5 c.844C>T variant is predicted to result in premature protein termination (p.Arg282*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with systemic primary carnitine deficiency (see, for example, Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371; Frigeni et al. 2017. PubMed ID: 28841266; Lamhonwah et al. 2018. PubMed ID: 29636919; Lin et al. 2021. PubMed ID: 34863234). In vitro functional studies demonstrate that this variant results in a loss of protein expression and carnitine transport activity (Wang et al. 1999. PubMed ID: 10051646; Vaz et al. 1999. PubMed ID: 10480371). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. Nonsense variants in SLC22A5 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
41
DANN
Uncertain
0.99
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Benign
0.74
D
MutationTaster
Benign
1.0
A;A
Vest4
0.94
GERP RS
2.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.29
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.29
Position offset: 18

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: rs121908886; hg19: chr5-131722736; API