Variant summary: The ASPA c.859G>A (p.Ala287Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The C-domain of the protein forms a pocket that accommodates the acetyl group of NAA and puts severe restriction on the size of this portion of substrate. The tight pocket is formed by residues Thr-118, Gln-184, Phe-282, Glu-285, Ala-287, and Tyr-288. Thus, p.Ala287Thr is predicted to alter the hydrogen bonding network, which may lead to destabilization of interaction between the N- and C-domain (PMID: 17194761). This variant was found in 3/120632 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). ASPA c.859G>A has been reported in numerous patients with Canavan disease. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)
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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)
Variation ID: 188803 Accession: VCV000188803.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3499005 (GRCh38) [ NCBI UCSC ] 17: 3402299 (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 Mar 29, 2015 Oct 20, 2024 Jan 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000049.4:c.859G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Ala287Thr missense NM_001128085.1:c.859G>A NP_001121557.1:p.Ala287Thr missense NM_001321336.2:c.-74+14407C>T intron variant NM_001321337.2:c.-74+14407C>T intron variant NC_000017.11:g.3499005G>A NC_000017.10:g.3402299G>A NG_008399.2:g.30360G>A NG_008399.3:g.29897G>A P45381:p.Ala287Thr - Protein change
- A287T
- Other names
- -
- Canonical SPDI
- NC_000017.11:3499004:G:A
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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 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ASPA | - | - |
GRCh38 GRCh37 |
18 | 492 | |
| SPATA22 | - | - |
GRCh38 GRCh37 |
24 | 596 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 5, 2024 | RCV000169134.24 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 4, 2016 | RCV000587229.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2022 | RCV002262764.21 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001163420.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Aug 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Canavan Disease, Familial Form
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000694158.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The ASPA c.859G>A (p.Ala287Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more)
Variant summary: The ASPA c.859G>A (p.Ala287Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The C-domain of the protein forms a pocket that accommodates the acetyl group of NAA and puts severe restriction on the size of this portion of substrate. The tight pocket is formed by residues Thr-118, Gln-184, Phe-282, Glu-285, Ala-287, and Tyr-288. Thus, p.Ala287Thr is predicted to alter the hydrogen bonding network, which may lead to destabilization of interaction between the N- and C-domain (PMID: 17194761). This variant was found in 3/120632 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). ASPA c.859G>A has been reported in numerous patients with Canavan disease. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002033206.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely pathogenic
(May 24, 2014)
|
criteria provided, single submitter
Method: literature only
|
Spongy degeneration of central nervous system
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220349.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Nov 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001420927.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 287 of the ASPA protein (p.Ala287Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 287 of the ASPA protein (p.Ala287Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Canavan disease (PMID: 12638939, 16854607, 26992473). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188803). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Jun 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002545849.16
First in ClinVar: Jul 09, 2022 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
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Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Canavan Disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002093216.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 287 of the ASPA protein (p.Ala287Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Canavan disease (PMID: 12638939, 16854607, 26992473). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188803). 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 with a positive predictive value of 95%. 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: The ASPA c.859G>A (p.Ala287Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The C-domain of the protein forms a pocket that accommodates the acetyl group of NAA and puts severe restriction on the size of this portion of substrate. The tight pocket is formed by residues Thr-118, Gln-184, Phe-282, Glu-285, Ala-287, and Tyr-288. Thus, p.Ala287Thr is predicted to alter the hydrogen bonding network, which may lead to destabilization of interaction between the N- and C-domain (PMID: 17194761). This variant was found in 3/120632 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic ASPA variant (0.0079057). ASPA c.859G>A has been reported in numerous patients with Canavan disease. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 287 of the ASPA protein (p.Ala287Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Canavan disease (PMID: 12638939, 16854607, 26992473). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188803). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A case of Canavan disease with microcephaly. | Gowda VK | Brain & development | 2016 | PMID: 26992473 |
| Molecular characterisation and prenatal diagnosis of Asparto-acylase deficiency (Canavan disease)--report of two novel and two known mutations from the Indian subcontinent. | Bijarnia S | Indian journal of pediatrics | 2013 | PMID: 22878930 |
| Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease. | Sreevishnupriya K | Science China. Life sciences | 2012 | PMID: 23233226 |
| Chromosomal 17p13.3 microdeletion unmasking recessive Canavan disease mutation. | Cozzolino M | Molecular genetics and metabolism | 2011 | PMID: 22019069 |
| 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 |
| Rapid detection of three large novel deletions of the aspartoacylase gene in non-Jewish patients with Canavan disease. | Zeng BJ | Molecular genetics and metabolism | 2006 | PMID: 16854607 |
| 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 |
Text-mined citations for rs774323189 ...
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 10, 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.