The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried an additional pathogenic variant (Amat di San Filippo 2006, Li 2010). The p.Pro398Leu variant is reported at pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25411) and is observed in the general population at a low overall frequency of 0.01% (21/282862 alleles) in the Genome Aggregation Database. The proline at codon 398 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Still, both in vitro and in vivo functional analyses of this variant demonstrate reduced cDNA expression and significantly decreased carnitine transport activity (Amat di San Filippo 2006, Frigeni 2017). Additionally, several other missense variants in the adjacent codon (p.Arg399Gln, p.Arg399Trp) are reported in individuals affected with PCD and exhibit reduced transport activity (Frigeni 2017), suggesting functional importance of this region of the protein. Based on available information, the p.Pro398Leu variant is considered to be pathogenic. References: Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. 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.
ClinVar Genomic variation as it relates to human health
NM_003060.4(SLC22A5):c.1193C>T (p.Pro398Leu)
Germline
Classification
Help
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.
(11)
Help
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.
Pathogenic/Likely pathogenic
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003060.4(SLC22A5):c.1193C>T (p.Pro398Leu)
Variation ID: 25411 Accession: VCV000025411.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q31.1 5: 132390830 (GRCh38) [ NCBI UCSC ] 5: 131726522 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Sep 29, 2024 Sep 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003060.4:c.1193C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Pro398Leu missense NM_001308122.2:c.1265C>T NP_001295051.1:p.Pro422Leu missense NC_000005.10:g.132390830C>T NC_000005.9:g.131726522C>T NG_008982.2:g.26127C>T O76082:p.Pro398Leu - Protein change
- P422L
- Other names
- -
- Canonical SPDI
- NC_000005.10:132390829:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Exome Aggregation Consortium (ExAC) 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| SLC22A5 | - | - |
GRCh38 GRCh37 |
1174 | 1217 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 16, 2024 | RCV000022365.42 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 13, 2024 | RCV000224074.22 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Oct 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001433773.2
First in ClinVar: Sep 27, 2020 Last updated: Jan 08, 2022 |
Comment:
The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried … (more)
The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried an additional pathogenic variant (Amat di San Filippo 2006, Li 2010). The p.Pro398Leu variant is reported at pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25411) and is observed in the general population at a low overall frequency of 0.01% (21/282862 alleles) in the Genome Aggregation Database. The proline at codon 398 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Still, both in vitro and in vivo functional analyses of this variant demonstrate reduced cDNA expression and significantly decreased carnitine transport activity (Amat di San Filippo 2006, Frigeni 2017). Additionally, several other missense variants in the adjacent codon (p.Arg399Gln, p.Arg399Trp) are reported in individuals affected with PCD and exhibit reduced transport activity (Frigeni 2017), suggesting functional importance of this region of the protein. Based on available information, the p.Pro398Leu variant is considered to be pathogenic. References: Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. 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. (less)
|
|
|
Likely pathogenic
(Aug 27, 2014)
|
criteria provided, single submitter
Method: literature only
|
Renal carnitine transport defect
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220651.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226146.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP4, PM2, PM3_strong, PS3, PS4_moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020649.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000819827.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). This variant is present in population databases (rs144547521, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985; Invitae). 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: 25411). 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: 16652335). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004183399.2
First in ClinVar: Dec 24, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jun 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281277.1
First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016 |
|
|
|
Pathogenic
(Dec 30, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000111942.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
|
|
|
Likely pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002055821.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
|
|
|
Pathogenic
(Sep 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001803427.5
First in ClinVar: Aug 21, 2021 Last updated: Sep 29, 2024 |
Comment:
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: 23430858, … (more)
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: 23430858, 16652335, 25087612, 20574985, 23757202, 16602102, 28841266, 23379544, 35568002) (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary systemic carnitine deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462820.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
PP4, PM2, PM3_strong, PS3, PS4_moderate
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). This variant is present in population databases (rs144547521, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985; Invitae). 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: 25411). 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: 16652335). For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 23430858, 16652335, 25087612, 20574985, 23757202, 16602102, 28841266, 23379544, 35568002)
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. |
Comment:
The SLC22A5 c.1193C>T; p.Pro398Leu variant (rs144547521) is reported in the literature in multiple individuals affected with primary carnitine deficiency (PCD), several of whom also carried an additional pathogenic variant (Amat di San Filippo 2006, Li 2010). The p.Pro398Leu variant is reported at pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 25411) and is observed in the general population at a low overall frequency of 0.01% (21/282862 alleles) in the Genome Aggregation Database. The proline at codon 398 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Still, both in vitro and in vivo functional analyses of this variant demonstrate reduced cDNA expression and significantly decreased carnitine transport activity (Amat di San Filippo 2006, Frigeni 2017). Additionally, several other missense variants in the adjacent codon (p.Arg399Gln, p.Arg399Trp) are reported in individuals affected with PCD and exhibit reduced transport activity (Frigeni 2017), suggesting functional importance of this region of the protein. Based on available information, the p.Pro398Leu variant is considered to be pathogenic. References: Amat di San Filippo C et al. Pharmacological rescue of carnitine transport in primary carnitine deficiency. Hum Mutat. 2006 Jun;27(6):513-23. Frigeni M et al. Functional and molecular studies in primary carnitine deficiency. Hum Mutat. 2017 Dec;38(12):1684-1699. 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.
Comment:
PP4, PM2, PM3_strong, PS3, PS4_moderate
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 398 of the SLC22A5 protein (p.Pro398Leu). This variant is present in population databases (rs144547521, gnomAD 0.02%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 16652335, 20574985; Invitae). 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: 25411). 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: 16652335). For these reasons, this variant has been classified as Pathogenic.
Comment:
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: 23430858, 16652335, 25087612, 20574985, 23757202, 16602102, 28841266, 23379544, 35568002)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional and molecular studies in primary carnitine deficiency. | Frigeni M | Human mutation | 2017 | PMID: 28841266 |
| Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
| Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. | Li FY | Human mutation | 2010 | PMID: 20574985 |
| Pharmacological rescue of carnitine transport in primary carnitine deficiency. | Amat di San Filippo C | Human mutation | 2006 | PMID: 16652335 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC22A5 | - | - | - | - |
Text-mined citations for rs144547521 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.