Variant summary: SLC22A5 c.1196G>A (p.Arg399Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1196G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Wang_2001). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein resulted in markedly reduced carnitine transport compared to the wild-type OCTN2 (5%; Frigeni_2017, Wang_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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.1196G>A (p.Arg399Gln)
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.
Pathogenic
9
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.1196G>A (p.Arg399Gln)
Variation ID: 6424 Accession: VCV000006424.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.1 5: 132390833 (GRCh38) [ NCBI UCSC ] 5: 131726525 (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 Mar 8, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003060.4:c.1196G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003051.1:p.Arg399Gln missense NM_001308122.2:c.1268G>A NP_001295051.1:p.Arg423Gln missense NC_000005.10:g.132390833G>A NC_000005.9:g.131726525G>A NG_008982.2:g.26130G>A O76082:p.Arg399Gln - Protein change
- R399Q, R423Q
- Other names
- -
- Canonical SPDI
- NC_000005.10:132390832:G:A
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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.
-
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 8, 2024 | RCV000006793.27 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2021 | RCV001532526.29 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 5, 2021 | RCV002226444.9 |
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
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
(Jul 05, 2019)
|
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: SCV001360662.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: SLC22A5 c.1196G>A (p.Arg399Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. … (more)
Variant summary: SLC22A5 c.1196G>A (p.Arg399Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1196G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Wang_2001). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein resulted in markedly reduced carnitine transport compared to the wild-type OCTN2 (5%; Frigeni_2017, Wang_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 22, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV001821565.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
|
|
|
Pathogenic
(Dec 09, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001789318.1
First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021 |
Comment:
Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency … (more)
Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 28841266, 28711408, 11715001, 16652335, 27931018, 15714519, 28186590) (less)
|
|
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Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001228413.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). This variant is present in population databases (rs121908891, gnomAD 0.007%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6424). 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: 11715001). 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: 20027113, 20574985, 25132046, 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)
|
|
|
Pathogenic
(Mar 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201299.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001748128.20
First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
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Pathogenic
(Nov 01, 2001)
|
no assertion criteria provided
Method: literature only
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CARNITINE DEFICIENCY, SYSTEMIC PRIMARY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026989.3
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2015 |
Comment on evidence:
Wang et al. (2001) reported Iranian Jewish sibs with systemic primary carnitine deficiency (CDSP; 212140) who were homozygous for a G-to-A transition at nucleotide 1196 … (more)
Wang et al. (2001) reported Iranian Jewish sibs with systemic primary carnitine deficiency (CDSP; 212140) who were homozygous for a G-to-A transition at nucleotide 1196 in exon 7 of the SLC22A5 gene, resulting in an arginine-to-glutamine substitution at codon 399 (R399Q). Both parents were heterozygous for this mutation. The first sib presented at 2 years of age in coma during an episode of gastroenteritis, while her older sister had weakness of the proximal limb girdle musculature requiring physical therapy, and developmental delays involving language skills, concentration, and attention span. Starting her on carnitine resulted in marked improvement of muscle tone, general mood, alertness, activity, and concentration span. (less)
|
|
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Pathogenic
(Apr 05, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Carnitine deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002078346.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
|
|
|
Pathogenic
(Apr 05, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Renal carnitine transport defect
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002107468.1
First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022 |
|
Comment:
Comment:
Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 28841266, 28711408, 11715001, 16652335, 27931018, 15714519, 28186590)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). This variant is present in population databases (rs121908891, gnomAD 0.007%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6424). 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: 11715001). 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: 20027113, 20574985, 25132046, 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.
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.1196G>A (p.Arg399Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251466 control chromosomes (gnomAD). c.1196G>A has been reported in the literature in individuals affected with Systemic Primary Carnitine Deficiency (Frigeni_2017, Wang_2001). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant protein resulted in markedly reduced carnitine transport compared to the wild-type OCTN2 (5%; Frigeni_2017, Wang_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Expression of R399Q in CHO cells reduced carnitine transport to 5% of normal transport activity (Wang et al., 2001); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 28841266, 28711408, 11715001, 16652335, 27931018, 15714519, 28186590)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 399 of the SLC22A5 protein (p.Arg399Gln). This variant is present in population databases (rs121908891, gnomAD 0.007%). This missense change has been observed in individual(s) with primary carnitine deficiency (PMID: 11715001, 28841266). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6424). 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: 11715001). 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: 20027113, 20574985, 25132046, 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.
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 |
| 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 |
Text-mined citations for rs121908891 ...
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.