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
Consequence
ENST00000245407.8 stop_gained
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC22A5 | NM_003060.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
SLC22A5 | ENST00000245407.8 | c.844C>T | p.Arg282Ter | stop_gained | 5/10 | 1 | NM_003060.4 | ENSP00000245407 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251492Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135918
GnomAD4 exome AF: 0.0000561 AC: 82AN: 1461832Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45AN XY: 727224
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74324
ClinVar
Submissions by phenotype
Renal carnitine transport defect Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The 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 submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 02, 1999 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 21, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 22, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This 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 submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 27, 2018 | Variant 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 submitter | clinical testing | GeneDx | Jul 30, 2020 | Reported 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 submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2019 | - - |
SLC22A5-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 18, 2024 | The 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at