ClinVar Genomic variation as it relates to human health
NM_003060.4(SLC22A5):c.1195C>T (p.Arg399Trp)
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.1195C>T (p.Arg399Trp)
Variation ID: 6427 Accession: VCV000006427.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132390832 (GRCh38) [ NCBI UCSC ] 5: 131726524 (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 Feb 20, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003060.4:c.1195C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Arg399Trp missense NM_001308122.2:c.1267C>T NP_001295051.1:p.Arg423Trp missense NC_000005.10:g.132390832C>T NC_000005.9:g.131726524C>T NG_008982.2:g.26129C>T O76082:p.Arg399Trp - Protein change
- R399W, R423W
- Other names
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- Canonical SPDI
- NC_000005.10:132390831:C:T
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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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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00012
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00047
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (9) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000006796.27 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 5, 2022 | RCV000186144.9 |
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
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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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Likely pathogenic
(Jun 08, 2016)
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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: SCV000342332.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Likely pathogenic
(Oct 25, 2018)
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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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Illumina Laboratory Services, Illumina
Accession: SCV000916082.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The SLC22A5 c.1195C>T (p.Arg399Trp) missense variant has been reported in at least four studies and was found in a total of at least nine individuals … (more)
The SLC22A5 c.1195C>T (p.Arg399Trp) missense variant has been reported in at least four studies and was found in a total of at least nine individuals who displayed low free carnitine levels, including in one in a homozygous state, in four in a compound heterozygous state, and in four in a heterozygous state with no second variant identified (El-Hattab et al. 2010; Li et al. 2010; Han et al. 2014; Gallant et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000566 in the Latino population of the Genome Aggregation Database. Based on the evidence, the p.Arg399Trp variant is classified as likely pathogenic for systemic primary carnitine deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Apr 26, 2018)
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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: SCV000920214.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
Variant summary: SLC22A5 c.1195C>T (p.Arg399Trp) 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.1195C>T (p.Arg399Trp) 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 0.00011 in 246242 control chromosomes. This frequency is not higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (0.00011 vs 0.0046), allowing no conclusion about variant significance. c.1195C>T has been reported in the literature in an individual affected with Systemic Primary Carnitine Deficiency (Frigeni_2017) as well as individuals with low carnitine levels who are asymptomatic (El-Hattab_2010, Han_2014). One publication reports experimental evidence showing a near total loss of carnitine transport in CHO cell and patient fibroblast assays (Frigeni_2017). Additionally, a variant at the same codon (p.Arg399Gln) has been reported as pathogenic in association with Systemic Primary Carnitine Deficiency, suggesting the Arg399 residue is important for function. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(May 10, 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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Revvity Omics, Revvity
Accession: SCV003821041.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jan 02, 2014)
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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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Counsyl
Accession: SCV000678005.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
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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
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Baylor Genetics
Accession: SCV001162980.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
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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: SCV002055823.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(May 05, 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: SCV000239170.11
First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023 |
Comment:
Functional analysis found this variant is associated with significantly impaired carnitine transport (Frigeni M et al., 2017); In silico analysis supports that this missense variant … (more)
Functional analysis found this variant is associated with significantly impaired carnitine transport (Frigeni M et al., 2017); 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: 29132460, 20027113, 26828774, 31302912, 33181153, 34178604, 32778825, 30863740, 28841266) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Renal carnitine transport defect
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Lifecell International Pvt. Ltd
Accession: SCV003925695.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
A Heterozygous Missense variant c.1195C>T in Exon 7 of the SLC22A5 gene that results in the amino acid substitution p.Arg399Trp was identified. The observed variant … (more)
A Heterozygous Missense variant c.1195C>T in Exon 7 of the SLC22A5 gene that results in the amino acid substitution p.Arg399Trp was identified. The observed variant has a minor allele frequency of 0.00012% in gnomAD exomes and is novel genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The observed variant is previously reported in patients affected with Primary Carnitine Deficiency (Frigeni, Marta et al., 2017). Furthermore, experimental studies have shown that this missense change affects SLC22A5 function (Longo, Nicola et al., 2016). ClinVar has also classified this variant as Pathogenic/ Likely Pathogenic [Variation ID:6427]. For these reasons, this variant has been classified as Pathogenic. (less)
Ethnicity/Population group: Asian
Geographic origin: India
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Pathogenic
(Jan 25, 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: SCV000816098.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the SLC22A5 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the SLC22A5 protein (p.Arg399Trp). This variant is present in population databases (rs267607054, gnomAD 0.06%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 20027113, 20574985, 25132046, 28841266). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 6427). 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: 27931018). This variant disrupts the p.Arg399 amino acid residue in SLC22A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11715001, 27931018, 28841266). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 29, 2015)
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no assertion criteria provided
Method: literature only
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CARNITINE DEFICIENCY, SYSTEMIC PRIMARY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026992.2
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother … (more)
In an African American family in which an infant was identified as having low carnitine in newborn screening, subsequent analysis showed that the asymptomatic mother actually had systemic carnitine deficiency (CDSP; 212140), with a free plasma carnitine level of 1 micromol/L and a total plasma carnitine of 2 micromol/L. She was found to be compound heterozygous for a C-to-T transversion at nucleotide 1195 of the SLC22A5 gene, resulting in an arg-to-trp substitution at codon 399 (R399W), and a second missense mutation (A442I; 603377.0021). (less)
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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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Functional and molecular studies in primary carnitine deficiency. | Frigeni M | Human mutation | 2017 | PMID: 28841266 |
Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California. | Gallant NM | Molecular genetics and metabolism | 2017 | PMID: 28711408 |
Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle. | Longo N | Annals of nutrition & metabolism | 2016 | PMID: 27931018 |
Analysis of genetic mutations in Chinese patients with systemic primary carnitine deficiency. | Han L | European journal of medical genetics | 2014 | PMID: 25132046 |
Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. | Li FY | Human mutation | 2010 | PMID: 20574985 |
Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects. | El-Hattab AW | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20027113 |
Phenotype and genotype variation in primary carnitine deficiency. | Wang Y | Genetics in medicine : official journal of the American College of Medical Genetics | 2001 | PMID: 11715001 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC22A5 | - | - | - | - |
Text-mined citations for rs267607054 ...
HelpRecord last updated Mar 17, 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.