This sequence change creates a premature translational stop signal (p.Thr178Asnfs*34) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). This variant is present in population databases (rs727504156, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with sialic acid storage disorders (PMID: 10581036, 15805149). ClinVar contains an entry for this variant (Variation ID: 167693). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_012434.5(SLC17A5):c.533del (p.Thr178fs)
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.
(13)
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
13
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_012434.5(SLC17A5):c.533del (p.Thr178fs)
Variation ID: 167693 Accession: VCV000167693.21
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 6q13 6: 73638492 (GRCh38) [ NCBI UCSC ] 6: 74348215 (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 Jun 29, 2015 Jun 17, 2024 Mar 12, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_012434.5:c.533del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_036566.1:p.Thr178fs frameshift NM_012434.5:c.533delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_012434.4:c.533del NC_000006.12:g.73638492del NC_000006.11:g.74348215del NG_008272.1:g.20523del - Protein change
- T178fs
- Other names
-
p.T178Nfs*34
- Canonical SPDI
- NC_000006.12:73638491:G:
-
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), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00024
- 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. |
|||
| SLC17A5 | - | - |
GRCh38 GRCh37 |
566 | 663 | |
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 (2) |
no assertion criteria provided
|
Jun 21, 2022 | RCV000005968.5 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 24, 2021 | RCV000153956.13 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 12, 2024 | RCV000588857.13 |
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
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Salla disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001232860.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Thr178Asnfs*34) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Thr178Asnfs*34) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). This variant is present in population databases (rs727504156, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with sialic acid storage disorders (PMID: 10581036, 15805149). ClinVar contains an entry for this variant (Variation ID: 167693). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Salla disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163089.2
First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Salla disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699340.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The SLC17A5 c.533delC (p.Thr178Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense … (more)
Variant summary: The SLC17A5 c.533delC (p.Thr178Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/118852 control chromosomes at a frequency of 0.0000673, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). Multiple publications have cited the variant in compound heterozygote affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001480119.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Clinical Features:
Hypertelorism (present) , Bilateral talipes equinovarus (present) , Talipes (present) , Hypoplasia of the corpus callosum (present) , Drooling (present) , Leukoencephalopathy (present) , Axial … (more)
Hypertelorism (present) , Bilateral talipes equinovarus (present) , Talipes (present) , Hypoplasia of the corpus callosum (present) , Drooling (present) , Leukoencephalopathy (present) , Axial hypotonia (present) , Infantile muscular hypotonia (present) , Oral motor hypotonia (present) , Movement disorder (present) (less)
Sex: male
|
|
|
Pathogenic
(Aug 07, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490802.1
First in ClinVar: Jun 29, 2015 Last updated: Jun 29, 2015 |
Comment:
Published functional studies demonstrate a damaging effect in deficiency of lysosomal transport (Mancini et al., 1991); Frameshift variant predicted to result in protein truncation or … (more)
Published functional studies demonstrate a damaging effect in deficiency of lysosomal transport (Mancini et al., 1991); Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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); This variant is associated with the following publications: (PMID: 2010546, 10947946, 12709150, 15805149, 10581036, 31589614) (less)
|
|
|
Pathogenic
(Dec 11, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000203574.7
First in ClinVar: Feb 02, 2015 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Jun 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Salla disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001572959.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: male
|
|
|
Pathogenic
(Sep 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Salla disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002027577.1
First in ClinVar: Nov 29, 2021 Last updated: Nov 29, 2021 |
|
|
|
Likely pathogenic
(Jun 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022593.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Dec 01, 1999)
|
no assertion criteria provided
Method: literature only
|
INFANTILE SIALIC ACID STORAGE DISORDER
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026150.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 29, 2015 |
Comment on evidence:
In a French patient with infantile sialic acid storage disease (ISSD; 269920), Verheijen et al. (1999) found compound heterozygosity for 2 frameshift mutations in the … (more)
In a French patient with infantile sialic acid storage disease (ISSD; 269920), Verheijen et al. (1999) found compound heterozygosity for 2 frameshift mutations in the SLC17A5 gene: 533delC, deleting 1 bp from codon 178 and producing a frameshift resulting in 33 new amino acids, then premature termination; and a 148-bp deletion (1112-1259; 604322.0003) producing a frameshift resulting in 27 new amino acids, then premature termination. This French patient, designated DR, was reported earlier by Mancini et al. (1991). (less)
|
|
|
Likely pathogenic
(Sep 22, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Salla disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132286.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Jun 21, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Sialic acid storage disease, severe infantile type
Affected status: yes
Allele origin:
maternal
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV004812052.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
Clinical Features:
Macroglossia (present) , Coarse facial features (present) , Low-set ears (present) , Sensorineural hearing loss disorder (present) , Broad nasal tip (present) , Hyperopic astigmatism … (more)
Macroglossia (present) , Coarse facial features (present) , Low-set ears (present) , Sensorineural hearing loss disorder (present) , Broad nasal tip (present) , Hyperopic astigmatism (present) , Corneal crystals (present) , Dental crowding (present) , Microdontia (present) , Abnormal rib morphology (present) , Precocious puberty (present) , Irregular menstruation (present) , Optic nerve dysplasia (present) , Interphalangeal joint contracture of finger (present) , Dysarthria (present) , Global developmental delay (present) , Specific learning disability (present) , Flexion contracture (present) , Subcutaneous nodule (present) , Mitral valve prolapse (present) , Aortic valve stenosis (present) , Aortic regurgitation (present) , Pes planus (present) , Hammertoe (present) , Achilles tendon contracture (present) , Sleep abnormality (present) , Scoliosis (present) , Obstructive sleep apnea syndrome (present) , Thoracolumbar scoliosis (present) , Short stature (present) , Ascending tubular aorta aneurysm (present) , Dysplastic aortic valve (present) , Depressed nasal bridge (present) , Capillary hemangioma (present) , Lower limb muscle weakness (present) , Aplasia/Hypoplasia of the macula (present) , Anisocoria (present) , Facial hirsutism (present) , Retinal vascular tortuosity (present) , Esophoria (present) , Systolic heart murmur (present) , Hyperkeratotic papule (present) , Clubbing of fingers (present) , Thick hair (present) (less)
Age: 10-19 years
Sex: female
Tissue: Blood
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Salla disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453513.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: The SLC17A5 c.533delC (p.Thr178Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/118852 control chromosomes at a frequency of 0.0000673, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). Multiple publications have cited the variant in compound heterozygote affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect in deficiency of lysosomal transport (Mancini et al., 1991); Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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); This variant is associated with the following publications: (PMID: 2010546, 10947946, 12709150, 15805149, 10581036, 31589614)
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 creates a premature translational stop signal (p.Thr178Asnfs*34) in the SLC17A5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC17A5 are known to be pathogenic (PMID: 10581036, 10947946, 15172001). This variant is present in population databases (rs727504156, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with sialic acid storage disorders (PMID: 10581036, 15805149). ClinVar contains an entry for this variant (Variation ID: 167693). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The SLC17A5 c.533delC (p.Thr178Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent SLC17A5 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/118852 control chromosomes at a frequency of 0.0000673, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC17A5 variant (0.0023717). Multiple publications have cited the variant in compound heterozygote affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect in deficiency of lysosomal transport (Mancini et al., 1991); Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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); This variant is associated with the following publications: (PMID: 2010546, 10947946, 12709150, 15805149, 10581036, 31589614)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical, morphological, and molecular aspects of sialic acid storage disease manifesting in utero. | Froissart R | Journal of medical genetics | 2005 | PMID: 15805149 |
| 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 |
| Infantile sialic acid storage disease (ISSD): report of the first case detected in Poland. | Tylki-Szymańska A | Pediatrics international : official journal of the Japan Pediatric Society | 2003 | PMID: 12709150 |
| 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 |
| Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides. | Mancini GM | The Journal of clinical investigation | 1991 | PMID: 2010546 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC17A5 | - | - | - | - |
Text-mined citations for rs727504156 ...
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.