ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.454T>C (p.Cys152Arg)
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.454T>C (p.Cys152Arg)
Variation ID: 2606 Accession: VCV000002606.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3483520 (GRCh38) [ NCBI UCSC ] 17: 3386814 (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 Apr 4, 2013 Feb 14, 2024 Nov 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000049.4:c.454T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Cys152Arg missense NM_001128085.1:c.454T>C NP_001121557.1:p.Cys152Arg missense NM_001321336.2:c.-73-14122A>G intron variant NM_001321337.2:c.-73-14122A>G intron variant NC_000017.11:g.3483520T>C NC_000017.10:g.3386814T>C NG_008399.2:g.14875T>C NG_008399.3:g.14412T>C P45381:p.Cys152Arg - Protein change
- C152R
- Other names
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- Canonical SPDI
- NC_000017.11:3483519: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
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The frequency of the allele represented by this VCV record.
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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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ASPA | - | - |
GRCh38 GRCh37 |
13 | 475 | |
SPATA22 | - | - |
GRCh38 GRCh37 |
21 | 581 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Nov 6, 2023 | RCV000002724.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 20, 2023 | RCV003387712.1 |
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
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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
(Sep 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Canavan Disease, Familial Form
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100002.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: ASPA c.454T>C (p.Cys152Arg) 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: ASPA c.454T>C (p.Cys152Arg) 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 was absent in 251422 control chromosomes (gnomAD). c.454T>C has been reported in the literature in the homozygous state in an individual affected with Canavan Disease (Kaul_1995). These data indicate that the variant may be associated with disease. Publications report experimental evidence evaluating an impact on protein function in vitro and found the variant results in a severe loss in enzyme activity, approximately 0.5% of the wild type protein, and has reduced thermal and conformational stability (Kaul_1995, Zano_2013). Additionally, other variants affecting the same amino acid (i.e. C152W, C152Y) have been observed in affected individuals (HGMD database), at least one of which (C152W) has also been shown to have impaired enzyme activity in a functional study (Zano_2013), suggesting Cys152 is important for enzyme function. The following publications have been ascertained in the context of this evaluation (PMID: 7599639, 22850825). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 06, 2023)
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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: SCV004316156.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 152 of the ASPA protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 152 of the ASPA protein (p.Cys152Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Canavan disease (PMID: 7599639). ClinVar contains an entry for this variant (Variation ID: 2606). 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%. Experimental studies have shown that this missense change affects ASPA function (PMID: 7599639, 22850825). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Mar 22, 2022)
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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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3billion
Accession: SCV002318867.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with ASPA related disorder (ClinVar ID: VCV000002606 … (more)
Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with ASPA related disorder (ClinVar ID: VCV000002606 ). The variant has been reported to be in trans with a pathogenic variant as homozygous in at least one similarly affected unrelated individual(PMID: 7599639). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:8659549,12638939). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.917>=0.6, 3CNET: 0.887>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Global developmental delay (present) , Inappropriate crying (present)
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Likely pathogenic
(Aug 30, 2023)
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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: SCV004201660.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 01, 1995)
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no assertion criteria provided
Method: literature only
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CANAVAN DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000022882.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In an Arab child with Canavan disease (271900), Kaul et al. (1995) identified a 454T-C transition in the ASPA gene, resulting in a cys152-to-arg (C152R) … (more)
In an Arab child with Canavan disease (271900), Kaul et al. (1995) identified a 454T-C transition in the ASPA gene, resulting in a cys152-to-arg (C152R) amino acid substitution. This was the second missense mutation and the fifth mutation of any type to be described for the ASPA gene. (less)
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Pathogenic
(Oct 22, 2012)
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no assertion criteria provided
Method: clinical testing
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Spongy degeneration of central nervous system
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000778443.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
The observed variant c.454T>C (p.Cys152Arg) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by … (more)
The observed variant c.454T>C (p.Cys152Arg) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT and probably damaging by PolyPhen2. (less)
Observation 1:
Indication for testing: Previous child dies due to Canavan disease
Age: 30-39 years
Sex: female
Ethnicity/Population group: Muslim/Gujarati
Geographic origin: India
Method: The exon and exon-intron boundaries of the ASPA gene were bidirectionally sequenced using an automated sequencer.
Observation 2:
Indication for testing: Previous child died due to Canavan disease
Age: 30-39 years
Sex: male
Ethnicity/Population group: Muslim/Gujarati
Geographic origin: India
Method: The exon and exon-intron boundaries of the ASPA gene were bidirectionally sequenced using an automated sequencer.
Observation 3:
Indication for testing: Parents are carrier for c.454T>C (p.Cys152Arg) in exon 3 of ASPA gene which results in to an autosomal recessive Canavan disease
Ethnicity/Population group: Muslim/Gujarati
Geographic origin: India
Method: The exon and the exon-intron boundaries of the ASPA gene were bidirectionally sequenced using an automated sequencer.
Observation 4:
Indication for testing: Parents and elder sibling carrier for c.454T>C (p.Cys152Arg) variant in exon 3 of ASPA gene which results in an autosomal recessive Canavan disease
Ethnicity/Population group: Muslim/Gujarati
Geographic origin: India
Method: The exon and the exon-intron boundaries of the ASPA gene were bidirectionally sequenced using an automated sequencer.
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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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Relationship between enzyme properties and disease progression in Canavan disease. | Zano S | Journal of inherited metabolic disease | 2013 | PMID: 22850825 |
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 |
Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. | Kaul R | American journal of human genetics | 1996 | PMID: 8659549 |
Novel (cys152 > arg) missense mutation in an Arab patient with Canavan disease. | Kaul R | Human mutation | 1995 | PMID: 7599639 |
Text-mined citations for rs104894548 ...
HelpRecord last updated May 12, 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.