Variant summary: SLC22A5 c.1409C>T (p.Ser470Phe) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) 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 8e-06 in 251466 control chromosomes. c.1409C>T has been reported in the literature in the homozygous state in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Cheema_2020, ALghamdi_2018, Lamhonwah_2002). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in CHO cells reports experimental evidence that this variant results in 0 transport activity compared to wildtype (e.g. Frigeni_2017). This variant is also known as c.1481C>T(p.Ser494Phe). The following publications have been ascertained in the context of this evaluation (PMID: 30069296, 33083013, 28841266, 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_003060.4(SLC22A5):c.1409C>T (p.Ser470Phe)
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.
(9)
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(3); Uncertain significance(1)
Pathogenic(5); Likely pathogenic(3); Uncertain significance(1)
9
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003060.4(SLC22A5):c.1409C>T (p.Ser470Phe)
Variation ID: 25425 Accession: VCV000025425.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132392574 (GRCh38) [ NCBI UCSC ] 5: 131728266 (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 Oct 20, 2024 May 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003060.4:c.1409C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Ser470Phe missense NM_001308122.2:c.1481C>T NP_001295051.1:p.Ser494Phe missense NC_000005.10:g.132392574C>T NC_000005.9:g.131728266C>T NG_008982.2:g.27871C>T - Protein change
- S494F
- Other names
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p.Ser470Phe
- Canonical SPDI
- NC_000005.10:132392573:C:T
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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), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
May 15, 2024 | RCV000022381.22 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2019 | RCV000513827.24 |
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
(Jun 19, 2017)
|
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: SCV000610106.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
|
|
|
Uncertain significance
(May 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000799728.1
First in ClinVar: Jan 26, 2017 Last updated: Jan 26, 2017 |
|
|
|
Likely pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004203600.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(May 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005185754.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
Variant summary: SLC22A5 c.1409C>T (p.Ser470Phe) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. … (more)
Variant summary: SLC22A5 c.1409C>T (p.Ser470Phe) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) 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 8e-06 in 251466 control chromosomes. c.1409C>T has been reported in the literature in the homozygous state in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Cheema_2020, ALghamdi_2018, Lamhonwah_2002). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in CHO cells reports experimental evidence that this variant results in 0 transport activity compared to wildtype (e.g. Frigeni_2017). This variant is also known as c.1481C>T(p.Ser494Phe). The following publications have been ascertained in the context of this evaluation (PMID: 30069296, 33083013, 28841266, 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001416144.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). 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. ClinVar contains an entry for this variant (Variation ID: 25425). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 12210323). This variant is present in population databases (rs386134222, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 470 of the SLC22A5 protein (p.Ser470Phe). (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Primary carnitine deficiency
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424486.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
|
|
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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: SCV002055779.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Likely pathogenic
(Oct 03, 2022)
|
criteria provided, single submitter
Method: research, in vitro
|
Renal carnitine transport defect
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
|
Giacomini Lab, University of California, San Francisco
Accession: SCV002576583.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Observation 1: Observation 2:
Method: In vitro uptake assays in HEK293T cells transiently expressing the variant were used to measure variant function relative to the reference allele. Function is reported as a % of the wild-type (reference) SLC22A5/OCTN2 transporter with respect to uptake of C14-carnitine.
Result:
The variant has 1.98% function of the wild-type SLC22A5/OCTN2 transporter with respect to transport of C14-carnitine in vitro.
|
|
|
Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247715.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). 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. ClinVar contains an entry for this variant (Variation ID: 25425). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 12210323). This variant is present in population databases (rs386134222, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 470 of the SLC22A5 protein (p.Ser470Phe).
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:
Variant summary: SLC22A5 c.1409C>T (p.Ser470Phe) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) 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 8e-06 in 251466 control chromosomes. c.1409C>T has been reported in the literature in the homozygous state in multiple individuals affected with Systemic Primary Carnitine Deficiency (e.g. Cheema_2020, ALghamdi_2018, Lamhonwah_2002). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study in CHO cells reports experimental evidence that this variant results in 0 transport activity compared to wildtype (e.g. Frigeni_2017). This variant is also known as c.1481C>T(p.Ser494Phe). The following publications have been ascertained in the context of this evaluation (PMID: 30069296, 33083013, 28841266, 12210323). ClinVar contains an entry for this variant (Variation ID: 25425). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SLC22A5 function (PMID: 28841266). 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. ClinVar contains an entry for this variant (Variation ID: 25425). This missense change has been observed in individual(s) with carnitine deficiency (PMID: 12210323). This variant is present in population databases (rs386134222, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 470 of the SLC22A5 protein (p.Ser470Phe).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic testing in 1019 individuals from 349 Pakistani families results in high diagnostic yield and clinical utility. | Cheema H | NPJ genomic medicine | 2020 | PMID: 33083013 |
| A case of atypical systemic primary carnitine deficiency in Saudi Arabia. | Alghamdi A | Pediatric reports | 2018 | PMID: 30069296 |
| Functional and molecular studies in primary carnitine deficiency. | Frigeni M | Human mutation | 2017 | PMID: 28841266 |
| Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. | Lamhonwah AM | American journal of medical genetics | 2002 | PMID: 12210323 |
Text-mined citations for rs386134222 ...
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 Oct 20, 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.