ClinVar Genomic variation as it relates to human health
NM_012434.5(SLC17A5):c.819+1G>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_012434.5(SLC17A5):c.819+1G>A
Variation ID: 371127 Accession: VCV000371127.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q13 6: 73635381 (GRCh38) [ NCBI UCSC ] 6: 74345104 (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 Jan 6, 2017 Feb 14, 2024 Aug 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_012434.5:c.819+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001382629.1:c.588+1G>A splice donor NM_001382630.1:c.819+1G>A splice donor NM_001382631.1:c.840+1G>A splice donor NM_001382632.1:c.732+1G>A splice donor NM_001382633.1:c.819+1G>A splice donor NM_001382634.1:c.819+1G>A splice donor NM_001382635.1:c.816+1G>A splice donor NM_001382636.1:c.501+1G>A splice donor NC_000006.12:g.73635381C>T NC_000006.11:g.74345104C>T NG_008272.1:g.23634G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000006.12:73635380:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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SLC17A5 | - | - |
GRCh38 GRCh37 |
553 | 650 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 13, 2023 | RCV000412283.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2022 | RCV000437560.7 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV002509063.1 |
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
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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
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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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Pathogenic
(Nov 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000517212.4
First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Identified in a patient with clinical features consistent with SLC17A5-related disorder in published literature (Barmherzig et al., 2017; Lionel et al., 2018); This variant is associated with the following publications: (PMID: 28771251, 28662915) (less)
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002027574.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
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Likely pathogenic
(Jul 06, 2016)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000486624.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Aug 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201221.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jun 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003821030.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(May 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001395546.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 6 of the SLC17A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 6 of the SLC17A5 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371127). Disruption of this splice site has been observed in individual(s) with Salla disease (PMID: 28662915). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). (less)
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Pathogenic
(Nov 10, 2020)
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no assertion criteria provided
Method: clinical testing
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Salla disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002076730.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing, in vitro
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Intermediate-severe Salla disease
(Autosomal recessive inheritance)
Affected status: yes, not applicable
Allele origin:
inherited,
not applicable
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MyeliNeuroGene Lab, McGill University Health Center Research Institute
Accession: SCV002540767.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
The c.819+1G>A variant in SLC17A5 has previously been reported in an individual with Intermediate-severe Salla disease (Barmherzig et al. 2017).
Observation 1:
Clinical Features:
Abnormal facial shape (present) , Generalized hypotonia (present) , Motor delay (present) , Severe global developmental delay (present) , Dystonic disorder (present) , Cerebellar ataxia … (more)
Abnormal facial shape (present) , Generalized hypotonia (present) , Motor delay (present) , Severe global developmental delay (present) , Dystonic disorder (present) , Cerebellar ataxia (present) , Spasticity (present) , Drooling (present) , Dysphagia (present) , Seizure (present) (less)
Ethnicity/Population group: French Canadian
Method: Whole exome sequencing was performed on the patients. Two variants were found in the SLC17A5 gene and were confirmed by Sanger sequencing. Co-segregation analysis of the candidate mutations was performed by sequencing the corresponding amplicon in available family members. Both of the variants had been previously confirmed as pathogenic, prompting diagnosis of intermediate-severe Salla disease.
Observation 2:
Comment on evidence:
RNA was extracted from an Intermediate-severe Salla disease patient's fibroblasts and reverse transcribed to cDNA. Amplification of cDNA surrounding the c.819+1G>A variant, followed by gel … (more)
RNA was extracted from an Intermediate-severe Salla disease patient's fibroblasts and reverse transcribed to cDNA. Amplification of cDNA surrounding the c.819+1G>A variant, followed by gel electrophoresis revealed an addition product in the patient sample compared to the control. Gel bands were excised and sent for Sanger sequencing. (less)
Result:
Functional splice site study analysis revealed the c.819+1G>A variant as a donor splice site mutation resulting in the deletion of exon 6. This deletion is out of frame and is predicted to cause a premature stop codon producing a truncated protein.
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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MyeliNeuroGene Lab, McGill University Health Center Research Institute
Accession: SCV002540767.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A New Patient With Intermediate Severe Salla Disease With Hypomyelination: A Literature Review for Salla Disease. | Barmherzig R | Pediatric neurology | 2017 | PMID: 28662915 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity. | Kleta R | Molecular genetics and metabolism | 2004 | PMID: 15172001 |
The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. | Aula N | American journal of human genetics | 2000 | PMID: 10947946 |
A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. | Verheijen FW | Nature genetics | 1999 | PMID: 10581036 |
- | - | - | - | DOI: 10.1016/j.pediatrneurol.2017.05.022 |
Text-mined citations for rs1057517028 ...
HelpRecord last updated Mar 17, 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.