Variant summary: SLC22A5 c.67_69delTTC (p.Phe23del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 2.6e-05 in 116020 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (2.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.67_69delTTC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency, in which patients were found to have <10% fibroblast carnitine transporter activity (Frigeni_2017, Lamhonwah_2002, Shibbani_2014). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. 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.64TTC[1] (p.Phe23del)
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.
(10)
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
10
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.64TTC[1] (p.Phe23del)
Variation ID: 25353 Accession: VCV000025353.40
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 5q31.1 5: 132370034-132370036 (GRCh38) [ NCBI UCSC ] 5: 131705726-131705728 (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 Oct 20, 2024 Feb 11, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003060.4:c.64TTC[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Phe23del inframe deletion NM_003060.4:c.67_69del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003060.4:c.67_69delTTC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001308122.2:c.64TTC[1] NP_001295051.1:p.Phe23del inframe deletion NM_003060.3:c.67_69del NC_000005.10:g.132370036TTC[1] NC_000005.9:g.131705728TTC[1] NG_008982.2:g.5333TTC[1] - Protein change
- F23del
- Other names
- -
- Canonical SPDI
- NC_000005.10:132370033:TCTTCTTC:TCTTC
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 (8) |
criteria provided, multiple submitters, no conflicts
|
Feb 11, 2024 | RCV000022300.25 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV001532525.22 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003821075.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Feb 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201271.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 16, 2018)
|
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: SCV000920212.1
First in ClinVar: May 31, 2019 Last updated: May 31, 2019 |
Comment:
Variant summary: SLC22A5 c.67_69delTTC (p.Phe23del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele … (more)
Variant summary: SLC22A5 c.67_69delTTC (p.Phe23del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 2.6e-05 in 116020 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (2.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.67_69delTTC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency, in which patients were found to have <10% fibroblast carnitine transporter activity (Frigeni_2017, Lamhonwah_2002, Shibbani_2014). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000632563.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant, c.67_69del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Phe23del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.67_69del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Phe23del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765192896, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 12210323, 16830263; 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: 25353). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC22A5 function (PMID: 2235122, 12210323). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003803372.2
First in ClinVar: Feb 18, 2023 Last updated: Sep 29, 2024 |
Comment:
Functional analysis found c.67_69delTTC is associated with significantly impaired carnitine transport (PMID: 21922592); In-frame deletion of one amino acid in a non-repeat region predicted to … (more)
Functional analysis found c.67_69delTTC is associated with significantly impaired carnitine transport (PMID: 21922592); In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26828774, 21922592, 23379544, 23322164, 16830263, 28611029, 29895548, 28841266, 32778825, 12210323) (less)
|
|
|
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: SCV002055787.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Pathogenic
(Dec 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002816193.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Aug 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001748127.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Dec 08, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132291.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary systemic carnitine deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458680.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This variant, c.67_69del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Phe23del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765192896, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 12210323, 16830263; 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: 25353). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC22A5 function (PMID: 2235122, 12210323). For these reasons, this variant has been classified as Pathogenic.
Comment:
Functional analysis found c.67_69delTTC is associated with significantly impaired carnitine transport (PMID: 21922592); In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26828774, 21922592, 23379544, 23322164, 16830263, 28611029, 29895548, 28841266, 32778825, 12210323)
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.67_69delTTC (p.Phe23del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 2.6e-05 in 116020 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC22A5 causing Systemic Primary Carnitine Deficiency (2.6e-05 vs 0.0046), allowing no conclusion about variant significance. c.67_69delTTC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency, in which patients were found to have <10% fibroblast carnitine transporter activity (Frigeni_2017, Lamhonwah_2002, Shibbani_2014). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant, c.67_69del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Phe23del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs765192896, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 12210323, 16830263; 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: 25353). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SLC22A5 function (PMID: 2235122, 12210323). For these reasons, this variant has been classified as Pathogenic.
Comment:
Functional analysis found c.67_69delTTC is associated with significantly impaired carnitine transport (PMID: 21922592); In-frame deletion of one amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26828774, 21922592, 23379544, 23322164, 16830263, 28611029, 29895548, 28841266, 32778825, 12210323)
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 |
| Primary carnitine deficiency: novel mutations and insights into the cardiac phenotype. | Shibbani K | Clinical genetics | 2014 | PMID: 23379544 |
| Genotype-phenotype correlation in primary carnitine deficiency. | Rose EC | Human mutation | 2012 | PMID: 21922592 |
| Pericardial effusion in primary systemic carnitine deficiency. | Wattanasirichaigoon D | Journal of inherited metabolic disease | 2006 | PMID: 16830263 |
| Pharmacological rescue of carnitine transport in primary carnitine deficiency. | Amat di San Filippo C | Human mutation | 2006 | PMID: 16652335 |
| Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. | Lamhonwah AM | American journal of medical genetics | 2002 | PMID: 12210323 |
| Impaired skin fibroblast carnitine uptake in primary systemic carnitine deficiency manifested by childhood carnitine-responsive cardiomyopathy. | Tein I | Pediatric research | 1990 | PMID: 2235122 |
Text-mined citations for rs377767444 ...
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.