ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.47T>C (p.Ile16Thr)
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_000049.4(ASPA):c.47T>C (p.Ile16Thr)
Variation ID: 550560 Accession: VCV000550560.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3476206 (GRCh38) [ NCBI UCSC ] 17: 3379500 (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 Aug 5, 2018 Jun 17, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000049.4:c.47T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Ile16Thr missense NM_001128085.1:c.47T>C NP_001121557.1:p.Ile16Thr missense NM_001321336.2:c.-73-6808A>G intron variant NM_001321337.2:c.-73-6808A>G intron variant NC_000017.11:g.3476206T>C NC_000017.10:g.3379500T>C NG_008399.3:g.7098T>C - Protein change
- I16T
- Other names
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- Canonical SPDI
- NC_000017.11:3476205:T:C
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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 | ||
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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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ASPA | - | - |
GRCh38 GRCh37 |
18 | 489 | |
SPATA22 | - | - |
GRCh38 GRCh37 |
21 | 590 |
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
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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 (6) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2024 | RCV000665338.21 |
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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Likely pathogenic
(Feb 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000789444.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: yes
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002033128.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Likely pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809068.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001584905.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). In at least one individual the data is consistent with being … (more)
This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). 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 ASPA protein function. ClinVar contains an entry for this variant (Variation ID: 550560). This variant is present in population databases (rs769653717, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 16 of the ASPA protein (p.Ile16Thr). (less)
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Likely pathogenic
(Jan 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201760.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Likely Pathogenic
(May 10, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848646.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ile16Thr variant in ASPA has been reported in compound heterozygous state with another pathogenic ASPA variant in 3 individuals with Canavan Disease (Kaul 1996 … (more)
The p.Ile16Thr variant in ASPA has been reported in compound heterozygous state with another pathogenic ASPA variant in 3 individuals with Canavan Disease (Kaul 1996 PMID: 8659549, Elpeleg 1999 PMID: 10407784, Zeng 2002 PMID: 12638939). It at least 1 individual, the Ile16Thr variant was confirmed to be in trans. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 550560) and has been identified in 0.002% (2/113756) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies of enzyme activity provide evidence that this variant affects protein function, as its enzymatic activity was 0.4% of the wild type allele (Kaul 1996 PMID: 8659549). Computational prediction tools and conservation analyses do not provide evidence for or against an effect to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Canavan Disease. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PS3_Moderate. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease. | Sreevishnupriya K | Science China. Life sciences | 2012 | PMID: 23233226 |
Structure of aspartoacylase, the brain enzyme impaired in Canavan disease. | Bitto E | Proceedings of the National Academy of Sciences of the United States of America | 2007 | PMID: 17194761 |
Mutation analysis of the aspartoacylase gene in non-Jewish patients with Canavan disease. | Zeng BJ | Advances in experimental medicine and biology | 2006 | PMID: 16802711 |
Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. | Zeng BJ | Journal of inherited metabolic disease | 2002 | PMID: 12638939 |
The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients. | Elpeleg ON | Journal of inherited metabolic disease | 1999 | PMID: 10407784 |
Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. | Kaul R | American journal of human genetics | 1996 | PMID: 8659549 |
Text-mined citations for rs769653717 ...
HelpRecord last updated Aug 18, 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.