Variant summary: ASPA c.820G>A (p.Gly274Arg) 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 allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD). c.820G>A has been reported in the literature in multiple homozygous individuals affected with Canavan Disease (Shaag_1995, Tacke_2005, Hussain_2012, Cakar_2020). In addition, in one Pakistani family, the variant co-segregated with the disease (Hussain_2012). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in decreasing normal aspartoacylase activity and conformational stability (Zano_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.820G>A (p.Gly274Arg)
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.820G>A (p.Gly274Arg)
Variation ID: 188788 Accession: VCV000188788.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3498966 (GRCh38) [ NCBI UCSC ] 17: 3402260 (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 Jun 17, 2024 Dec 17, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000049.4:c.820G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Gly274Arg missense NM_001128085.1:c.820G>A NP_001121557.1:p.Gly274Arg missense NM_001321336.2:c.-74+14446C>T intron variant NM_001321337.2:c.-74+14446C>T intron variant NC_000017.11:g.3498966G>A NC_000017.10:g.3402260G>A NG_008399.2:g.30321G>A NG_008399.3:g.29858G>A P45381:p.Gly274Arg - Protein change
- G274R
- Other names
- -
- Canonical SPDI
- NC_000017.11:3498965:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 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
|
Dec 17, 2023 | RCV000169117.23 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 10, 2022 | RCV001293576.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 28, 2022 | RCV002222420.10 |
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
(Dec 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201638.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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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: SCV002033173.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Pathogenic
(Nov 10, 2022)
|
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: SCV001482182.2
First in ClinVar: Mar 07, 2021 Last updated: Dec 24, 2022 |
Comment:
Variant summary: ASPA c.820G>A (p.Gly274Arg) 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.820G>A (p.Gly274Arg) 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 allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD). c.820G>A has been reported in the literature in multiple homozygous individuals affected with Canavan Disease (Shaag_1995, Tacke_2005, Hussain_2012, Cakar_2020). In addition, in one Pakistani family, the variant co-segregated with the disease (Hussain_2012). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in decreasing normal aspartoacylase activity and conformational stability (Zano_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(May 16, 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: SCV000220320.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Mar 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811720.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002499794.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate G274R results in significantly reduced, but not absent, ASPA activity (Hershfield et al., 2007; Zano et al., 2013); Not observed at … (more)
Published functional studies demonstrate G274R results in significantly reduced, but not absent, ASPA activity (Hershfield et al., 2007; Zano et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23233226, 22850825, 7668285, 27457812, 17999961, 17194761, 10407784, 22219087, 17391648, 31839386, 16138249) (less)
|
|
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Pathogenic
(Feb 11, 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: SCV001394833.6
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the ASPA protein (p.Gly274Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the ASPA protein (p.Gly274Arg). This variant is present in population databases (rs761064915, gnomAD 0.002%). This missense change has been observed in individuals with Canavan disease (PMID: 7668285, 16138249, 22219087, 27457812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188788). 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. Experimental studies have shown that this missense change affects ASPA function (PMID: 22850825). For these reasons, this variant has been classified as Pathogenic. (less)
|
Comment:
Comment:
Published functional studies demonstrate G274R results in significantly reduced, but not absent, ASPA activity (Hershfield et al., 2007; Zano et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23233226, 22850825, 7668285, 27457812, 17999961, 17194761, 10407784, 22219087, 17391648, 31839386, 16138249)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the ASPA protein (p.Gly274Arg). This variant is present in population databases (rs761064915, gnomAD 0.002%). This missense change has been observed in individuals with Canavan disease (PMID: 7668285, 16138249, 22219087, 27457812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188788). 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. Experimental studies have shown that this missense change affects ASPA function (PMID: 22850825). 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: ASPA c.820G>A (p.Gly274Arg) 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 allele was found at a frequency of 8e-06 in 251168 control chromosomes (gnomAD). c.820G>A has been reported in the literature in multiple homozygous individuals affected with Canavan Disease (Shaag_1995, Tacke_2005, Hussain_2012, Cakar_2020). In addition, in one Pakistani family, the variant co-segregated with the disease (Hussain_2012). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in decreasing normal aspartoacylase activity and conformational stability (Zano_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate G274R results in significantly reduced, but not absent, ASPA activity (Hershfield et al., 2007; Zano et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23233226, 22850825, 7668285, 27457812, 17999961, 17194761, 10407784, 22219087, 17391648, 31839386, 16138249)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 274 of the ASPA protein (p.Gly274Arg). This variant is present in population databases (rs761064915, gnomAD 0.002%). This missense change has been observed in individuals with Canavan disease (PMID: 7668285, 16138249, 22219087, 27457812). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188788). 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. Experimental studies have shown that this missense change affects ASPA function (PMID: 22850825). 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 juvenile Canavan disease with distinct pons involvement. | Çakar NE | Brain & development | 2020 | PMID: 31839386 |
| Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. | Riazuddin S | Molecular psychiatry | 2017 | PMID: 27457812 |
| Relationship between enzyme properties and disease progression in Canavan disease. | Zano S | Journal of inherited metabolic disease | 2013 | PMID: 22850825 |
| Computational analysis of deleterious missense mutations in aspartoacylase that cause Canavan's disease. | Sreevishnupriya K | Science China. Life sciences | 2012 | PMID: 23233226 |
| A missense mutation (p.G274R) in gene ASPA causes Canavan disease in a Pakistani family. | Hussain R | Molecular biology reports | 2012 | PMID: 22219087 |
| Novel mutation of aspartoacylase gene in a Turkish patient with Canavan disease. | Unalp A | Journal of tropical pediatrics | 2008 | PMID: 17999961 |
| Mutational analysis of aspartoacylase: implications for Canavan disease. | Hershfield JR | Brain research | 2007 | PMID: 17391648 |
| 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 |
| Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. | Tacke U | Neuropediatrics | 2005 | PMID: 16138249 |
| 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 |
| The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients. | Shaag A | American journal of human genetics | 1995 | PMID: 7668285 |
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Text-mined citations for rs761064915 ...
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.