ClinVar Genomic variation as it relates to human health
NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003060.4(SLC22A5):c.1400C>G (p.Ser467Cys)
Variation ID: 25423 Accession: VCV000025423.55
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132392565 (GRCh38) [ NCBI UCSC ] 5: 131728257 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 23, 2014 May 12, 2024 Feb 5, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003060.4:c.1400C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Ser467Cys missense NM_001308122.2:c.1472C>G NP_001295051.1:p.Ser491Cys missense NC_000005.10:g.132392565C>G NC_000005.9:g.131728257C>G NG_008982.2:g.27862C>G O76082:p.Ser467Cys - Protein change
- S491C
- Other names
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- Canonical SPDI
- NC_000005.10:132392564:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00009
Trans-Omics for Precision Medicine (TOPMed) 0.00015
Exome Aggregation Consortium (ExAC) 0.00016
The Genome Aggregation Database (gnomAD), exomes 0.00017
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC22A5 | - | - |
GRCh38 GRCh37 |
1156 | 1198 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Feb 5, 2024 | RCV000022379.38 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 19, 2022 | RCV000414447.36 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jan 29, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000111945.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001162982.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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Pathogenic
(May 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001433772.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
Comment:
The SLC22A5 c.1400C>G; p.Ser467Cys variant (rs60376624) has been described in the homozygous and compound heterozygous states in individuals affected with primary carnitine deficiency or carnitine … (more)
The SLC22A5 c.1400C>G; p.Ser467Cys variant (rs60376624) has been described in the homozygous and compound heterozygous states in individuals affected with primary carnitine deficiency or carnitine uptake deficiency (Koizumi 1999, Li 2010, Rose 2012, Yoon 2012). It is reported as pathogenic in ClinVar (Variation ID: 25423) and observed in the East Asian population at an overall frequency of 0.2% (43/18870 alleles) in the Genome Aggregation Database. The serine at codon 467 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. Additionally, functional analyses of the variant protein demonstrate a significant reduction in L-carnitine uptake (Koizumi 1999, Rose 2012). Based on available information, this variant is considered pathogenic. References: Koizumi A et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999 Nov;8(12):2247-54. Li F et al. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Hum Mutat. 2010 Aug;31(8):E1632-51. Rose E et al. Genotype-phenotype correlation in primary carnitine deficiency. Hum Mutat. 2012 Jan;33(1):118-23. Yoon Y et al. SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation. Ann Clin Lab Sci. 2012 Fall;42(4):424-8. (less)
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Likely pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002055829.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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Pathogenic
(Jan 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074341.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Comment:
Variant summary: SLC22A5 c.1400C>G (p.Ser467Cys) results in a non-conservative amino acid change located in the major facilitator superfamily domain of the encoded protein sequence. Five … (more)
Variant summary: SLC22A5 c.1400C>G (p.Ser467Cys) results in a non-conservative amino acid change located in the major facilitator superfamily domain 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 0.00017 in 251468 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00017 vs 0.0046), allowing no conclusion about variant significance. c.1400C>G is a common pathogenic mutation found in individuals with primary carnitine deficiency or carnitine uptake defect (ie. Koizumi_1999, Lin_2020). In vitro functional analysis revealed the variant to reduce L-carnitine uptake to 11% of the normal control (Koizumi_2020). Eight 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002790443.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490806.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
In vitro expression studies in HEK cells indicate that S467C has significantly reduced L-carnitine uptake relative to a normal control (Koizumi et al., 1999); In … (more)
In vitro expression studies in HEK cells indicate that S467C has significantly reduced L-carnitine uptake relative to a normal control (Koizumi et al., 1999); 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: 28186590, 20208395, 25377941, 26589311, 25846890, 23090741, 12183691, 10545605, 26828774, 27317853, 29581464, 28841266, 20074989, 20574985, 29132460, 30885166, 30863740, 31637888, 32595695, 33757571, 33560599, 33181153) (less)
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Pathogenic
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000632528.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 467 of the SLC22A5 protein … (more)
This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 467 of the SLC22A5 protein (p.Ser467Cys). This variant is present in population databases (rs60376624, gnomAD 0.2%). This missense change has been observed in individuals with SLC22A5-related conditions (PMID: 10545605, 20074989, 20574985, 21922592, 23090741). ClinVar contains an entry for this variant (Variation ID: 25423). 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: 10545605, 12183691). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247713.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 2
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Likely pathogenic
(Jan 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001193898.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_003060.3(SLC22A5):c.1400C>G(S467C) is classified as likely pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID: 30904546, 28841266, 20074989, 23090741, … (more)
NM_003060.3(SLC22A5):c.1400C>G(S467C) is classified as likely pathogenic in the context of primary carnitine deficiency. Sources cited for classification include the following: PMID: 30904546, 28841266, 20074989, 23090741, 10545605 and 12183691. Classification of NM_003060.3(SLC22A5):c.1400C>G(S467C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Aug 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022599.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 05, 2024)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812654.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in SLC22A5 is predicted to replace serine with serine at codon cysteine, p.(Ser467Cys). The serine residue is highly conserved (100 vertebrates, Multiz … (more)
This sequence change in SLC22A5 is predicted to replace serine with serine at codon cysteine, p.(Ser467Cys). The serine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the transmembrane major facilitator superfamily (MFS) profile domain. There is a large physicochemical difference between serine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.2% (98/44,876 alleles) in the East Asian population. This variant has been detected in the homozygous and compound heterozygous state in multiple individuals with a diagnosis of systemic carnitine deficiency (SCD) mainly ascertained through newborn screening and asymptomatic (PMID: 20574985, 25846890, 21922592, 28841266, 37628339). The variant segregates with SCD in at least one family (PMID: 25846890). In vitro functional assays with limited validation in mammalian cell lines demonstrate the variant significantly reduces carnitine uptake (PMID: 10545605, 28841266). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.756). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1, PP3, PS3_Supporting. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Primary systemic carnitine deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462823.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Renal carnitine transport defect
Affected status: yes
Allele origin:
germline
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Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital
Accession: SCV004800872.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
PS3+PM3_S+PP1_S+PP3+PP4
Observation 1:
Number of individuals with the variant: 1
Ethnicity/Population group: Han
Geographic origin: China
Observation 2:
Number of individuals with the variant: 1
Ethnicity/Population group: Han
Geographic origin: China
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A Study of Maternal Patients Diagnosed with Inborn Errors of Metabolism Due to Positive Newborn Mass Screening in Their Newborns. | Onuki T | Children (Basel, Switzerland) | 2023 | PMID: 37628339 |
Screening 3.4 million newborns for primary carnitine deficiency in Zhejiang Province, China. | Lin Y | Clinica chimica acta; international journal of clinical chemistry | 2020 | PMID: 32371215 |
Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population. | Lin Y | Clinica chimica acta; international journal of clinical chemistry | 2019 | PMID: 30904546 |
Functional and molecular studies in primary carnitine deficiency. | Frigeni M | Human mutation | 2017 | PMID: 28841266 |
Importance of molecular diagnosis in the accurate diagnosis of systemic carnitine deficiency. | Hitomi T | Journal of genetics | 2015 | PMID: 25846890 |
SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation. | Yoon YA | Annals of clinical and laboratory science | 2012 | PMID: 23090741 |
Genotype-phenotype correlation in primary carnitine deficiency. | Rose EC | Human mutation | 2012 | PMID: 21922592 |
Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. | Li FY | Human mutation | 2010 | PMID: 20574985 |
Diagnoses of newborns and mothers with carnitine uptake defects through newborn screening. | Lee NC | Molecular genetics and metabolism | 2010 | PMID: 20074989 |
Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein. | Ohashi R | The Journal of pharmacology and experimental therapeutics | 2002 | PMID: 12183691 |
Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. | Koizumi A | Human molecular genetics | 1999 | PMID: 10545605 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC22A5 | - | - | - | - |
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Text-mined citations for rs60376624 ...
HelpRecord last updated May 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.