The c.1181_1183delTGC variant has not been published as a benign polymorphism to our knowledge. It is listed in the ARUP SLC22A5 database as a pathogenic variant (http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php). The c.1181_1183delTGC deletion causes the loss of a single Leucine residue at amino acid position 394, denoted p.Leu394del. The Leucine at position 394 is highly conserved through mammals, and missense variants in nearby residues (P398L, R399Q) have been reported in association with PCD, supporting the functional importance of this region of the protein. Therefore, the c.1181_1183delTGC variant was interpreted as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_003060.4(SLC22A5):c.1175TGC[2] (p.Leu394del)
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.
(7)
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
7
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.1175TGC[2] (p.Leu394del)
Variation ID: 25410 Accession: VCV000025410.18
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 5q31.1 5: 132390810-132390812 (GRCh38) [ NCBI UCSC ] 5: 131726502-131726504 (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 Jun 17, 2024 Mar 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003060.4:c.1173_1175del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_003060.4:c.1175TGC[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Leu394del inframe deletion NM_003060.4:c.1181_1183del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001308122.2:c.1247TGC[2] NP_001295051.1:p.Leu418del inframe deletion NM_003060.3:c.1181_1183del NC_000005.10:g.132390812TGC[2] NC_000005.9:g.131726504TGC[2] NG_008982.2:g.26109TGC[2] - Protein change
- L394del, L418del
- Other names
- -
- Canonical SPDI
- NC_000005.10:132390809:GCTGCTGCTGC:GCTGCTGC
-
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.
- -
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV000022364.23 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jun 20, 2017 | RCV000186156.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239182.3
First in ClinVar: Jul 18, 2015 Last updated: Dec 19, 2017 |
Comment:
The c.1181_1183delTGC variant has not been published as a benign polymorphism to our knowledge. It is listed in the ARUP SLC22A5 database as a pathogenic … (more)
The c.1181_1183delTGC variant has not been published as a benign polymorphism to our knowledge. It is listed in the ARUP SLC22A5 database as a pathogenic variant (http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php). The c.1181_1183delTGC deletion causes the loss of a single Leucine residue at amino acid position 394, denoted p.Leu394del. The Leucine at position 394 is highly conserved through mammals, and missense variants in nearby residues (P398L, R399Q) have been reported in association with PCD, supporting the functional importance of this region of the protein. Therefore, the c.1181_1183delTGC variant was interpreted as likely pathogenic. (less)
|
|
|
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: SCV002055820.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Likely pathogenic
(Feb 16, 2022)
|
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: SCV002103683.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Comment:
Variant summary: SLC22A5 c.1181_1183delTGC (p.Leu394del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele … (more)
Variant summary: SLC22A5 c.1181_1183delTGC (p.Leu394del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251484 control chromosomes. c.1181_1183delTGC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Echaniz-Laguna_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Frigeni_2017). Three 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 likely pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002804295.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004041295.2
First in ClinVar: Oct 07, 2023 Last updated: Jun 17, 2024 |
|
|
|
Likely pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816452.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000632516.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant, c.1181_1183del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Leu394del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.1181_1183del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Leu394del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762932965, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 26828774, 28841266, 29895548; 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: 25410). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
Variant summary: SLC22A5 c.1181_1183delTGC (p.Leu394del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251484 control chromosomes. c.1181_1183delTGC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Echaniz-Laguna_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Frigeni_2017). Three 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 likely pathogenic.
Comment:
This variant, c.1181_1183del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Leu394del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762932965, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 26828774, 28841266, 29895548; 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: 25410). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
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 c.1181_1183delTGC variant has not been published as a benign polymorphism to our knowledge. It is listed in the ARUP SLC22A5 database as a pathogenic variant (http://www.arup.utah.edu/database/OCTN2/OCTN2_welcome.php). The c.1181_1183delTGC deletion causes the loss of a single Leucine residue at amino acid position 394, denoted p.Leu394del. The Leucine at position 394 is highly conserved through mammals, and missense variants in nearby residues (P398L, R399Q) have been reported in association with PCD, supporting the functional importance of this region of the protein. Therefore, the c.1181_1183delTGC variant was interpreted as likely pathogenic.
Comment:
Variant summary: SLC22A5 c.1181_1183delTGC (p.Leu394del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.6e-05 in 251484 control chromosomes. c.1181_1183delTGC has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Echaniz-Laguna_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Frigeni_2017). Three 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 likely pathogenic.
Comment:
This variant, c.1181_1183del, results in the deletion of 1 amino acid(s) of the SLC22A5 protein (p.Leu394del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs762932965, gnomAD 0.009%). This variant has been observed in individual(s) with primary carnitine deficiency (PMID: 26828774, 28841266, 29895548; 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: 25410). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Primary carnitine deficiency in a 57-year-old patient with recurrent exertional rhabdomyolysis. | Echaniz-Laguna A | BMJ case reports | 2018 | PMID: 29895548 |
| Functional and molecular studies in primary carnitine deficiency. | Frigeni M | Human mutation | 2017 | PMID: 28841266 |
| Carnitine transport and fatty acid oxidation. | Longo N | Biochimica et biophysica acta | 2016 | PMID: 26828774 |
Text-mined citations for rs386134215 ...
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 Sep 29, 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.