This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein (p.Arg457Trp). This variant is present in population databases (rs761533681, gnomAD 0.05%). This missense change has been observed in individuals with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 2837306, 26041762; Invitae). ClinVar contains an entry for this variant (Variation ID: 372158). 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 SLC1A4 protein function. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). This variant disrupts the p.Arg457 amino acid residue in SLC1A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC1A4-related conditions (PMID: 26041762, 34174466), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_003038.5(SLC1A4):c.1369C>T (p.Arg457Trp)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003038.5(SLC1A4):c.1369C>T (p.Arg457Trp)
Variation ID: 372158 Accession: VCV000372158.46
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p14 2: 65020916 (GRCh38) [ NCBI UCSC ] 2: 65248050 (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 Jan 7, 2017 Oct 20, 2024 Sep 10, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003038.5:c.1369C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003029.2:p.Arg457Trp missense NM_001193493.2:c.475C>T NP_001180422.1:p.Arg159Trp missense NM_001348406.2:c.709C>T NP_001335335.1:p.Arg237Trp missense NM_001348407.2:c.709C>T NP_001335336.1:p.Arg237Trp missense NC_000002.12:g.65020916C>T NC_000002.11:g.65248050C>T NG_053002.1:g.37472C>T - Protein change
- R457W, R237W, R159W
- Other names
- -
- Canonical SPDI
- NC_000002.12:65020915: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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00012
Exome Aggregation Consortium (ExAC) 0.00016
- 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. |
|||
| SLC1A4 | - | - |
GRCh38 GRCh37 |
388 | 407 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 3, 2023 | RCV000412526.7 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 10, 2024 | RCV000436990.34 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 4, 2017 | RCV000623105.3 |
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
(May 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742357.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Microcephaly (present) , Failure to thrive (present) , Feeding difficulties (present) , Muscular hypotonia (present) , Flexion contracture (present) , … (more)
Global developmental delay (present) , Microcephaly (present) , Failure to thrive (present) , Feeding difficulties (present) , Muscular hypotonia (present) , Flexion contracture (present) , Clonus (present) , Abnormality of the hairline (present) , Microretrognathia (present) , Irregular dentition (present) , Delayed myelination (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
|
|
|
Likely pathogenic
(Oct 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001489771.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein (p.Arg457Trp). This variant is present in population databases (rs761533681, gnomAD 0.05%). This missense change has been observed in individuals with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 2837306, 26041762; Invitae). ClinVar contains an entry for this variant (Variation ID: 372158). 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 SLC1A4 protein function. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). This variant disrupts the p.Arg457 amino acid residue in SLC1A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC1A4-related conditions (PMID: 26041762, 34174466), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
|
Pathogenic
(Sep 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000525101.8
First in ClinVar: Mar 08, 2017 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); 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: 31763347, 26041762, Stehantsev2021[article], 33310157, 34174466, 37194416, 28327206, 2837306) (less)
|
|
|
Likely pathogenic
(Dec 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246774.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
SLC1A4: PM2, PM3, PP3, PS4:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Aug 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039321.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in 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 0.00012 in 251166 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in the homozygous state in two unrelated individuals affected with Spastic Tetraplegia-Thin Corpus Callosum-Progressive Postnatal Microcephaly Syndrome (Damseh_2015, Eldomery_2017). These data indicate that the variant is likely to be associated with disease. A functional study found that although the variant protein is expressed at a similar level as the WT protein at the plasma membrane, it has no detectable transport activity (Damseh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26041762, 28327206). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Feb 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238660.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Spastic tetraplegia-thin corpus callosum-progressive postnatal microcephaly syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000494177.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment:
This variant was identified in an individual with developmental delay, microcephaly, corpus callosum agenesis, hypomyelination.
|
|
|
Pathogenic
(Jun 15, 2020)
|
no assertion criteria provided
Method: literature only
|
SPASTIC TETRAPLEGIA, THIN CORPUS CALLOSUM, AND PROGRESSIVE MICROCEPHALY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000490231.2
First in ClinVar: Jan 07, 2017 Last updated: Jun 18, 2020 |
Comment on evidence:
In a girl, born of consanguineous Palestinian parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Damseh et al. (2015) identified a … (more)
In a girl, born of consanguineous Palestinian parents, with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM; 616657), Damseh et al. (2015) identified a homozygous c.1369C-T transition (c.1369C-T, NM_003038) in the SLC1A4 gene, resulting in an arg457-to-trp (R457W) substitution at a highly conserved residue. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found in 19 of over 60,000 individuals in the ExAC database; no homozygotes were present in that cohort. In vitro functional expression studies in HEK cells showed no measurable substrate transport activity for the R457W variant. (less)
|
Comment:
Comment:
Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); 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: 31763347, 26041762, Stehantsev2021[article], 33310157, 34174466, 37194416, 28327206, 2837306)
Comment:
SLC1A4: PM2, PM3, PP3, PS4:Supporting
Comment:
Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in 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 0.00012 in 251166 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in the homozygous state in two unrelated individuals affected with Spastic Tetraplegia-Thin Corpus Callosum-Progressive Postnatal Microcephaly Syndrome (Damseh_2015, Eldomery_2017). These data indicate that the variant is likely to be associated with disease. A functional study found that although the variant protein is expressed at a similar level as the WT protein at the plasma membrane, it has no detectable transport activity (Damseh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26041762, 28327206). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant was identified in an individual with developmental delay, microcephaly, corpus callosum agenesis, hypomyelination.
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:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 457 of the SLC1A4 protein (p.Arg457Trp). This variant is present in population databases (rs761533681, gnomAD 0.05%). This missense change has been observed in individuals with spastic tetraplegia, thin corpus callosum, and progressive microcephaly (PMID: 2837306, 26041762; Invitae). ClinVar contains an entry for this variant (Variation ID: 372158). 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 SLC1A4 protein function. Experimental studies have shown that this missense change affects SLC1A4 function (PMID: 26041762). This variant disrupts the p.Arg457 amino acid residue in SLC1A4. Other variant(s) that disrupt this residue have been observed in individuals with SLC1A4-related conditions (PMID: 26041762, 34174466), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Comment:
Published functional studies demonstrate p.R457W impairs transporter activity (PMID: 26041762); 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: 31763347, 26041762, Stehantsev2021[article], 33310157, 34174466, 37194416, 28327206, 2837306)
Comment:
SLC1A4: PM2, PM3, PP3, PS4:Supporting
Comment:
Variant summary: SLC1A4 c.1369C>T (p.Arg457Trp) results in a non-conservative amino acid change in 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 0.00012 in 251166 control chromosomes (gnomAD). c.1369C>T has been reported in the literature in the homozygous state in two unrelated individuals affected with Spastic Tetraplegia-Thin Corpus Callosum-Progressive Postnatal Microcephaly Syndrome (Damseh_2015, Eldomery_2017). These data indicate that the variant is likely to be associated with disease. A functional study found that although the variant protein is expressed at a similar level as the WT protein at the plasma membrane, it has no detectable transport activity (Damseh_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26041762, 28327206). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This variant was identified in an individual with developmental delay, microcephaly, corpus callosum agenesis, hypomyelination.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Severe neurodevelopmental disorder with intractable seizures due to a novel SLC1A4 homozygous variant. | Sedláčková L | European journal of medical genetics | 2021 | PMID: 34174466 |
| Lessons learned from additional research analyses of unsolved clinical exome cases. | Eldomery MK | Genome medicine | 2017 | PMID: 28327206 |
| Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. | Damseh N | Journal of medical genetics | 2015 | PMID: 26041762 |
| Recurrence of hepatocellular carcinoma after liver retransplantation. | Klompmaker IJ | British medical journal (Clinical research ed.) | 1988 | PMID: 2837306 |
Text-mined citations for rs761533681 ...
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.