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NM_000049.4(ASPA):c.914C>A (p.Ala305Glu)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
10 (Most recent: Sep 20, 2019)
Last evaluated:
Feb 22, 2019
Accession:
VCV000002607.4
Variation ID:
2607
Description:
single nucleotide variant
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NM_000049.4(ASPA):c.914C>A (p.Ala305Glu)

Allele ID
17646
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17p13.2
Genomic location
17: 3499060 (GRCh38) GRCh38 UCSC
17: 3402354 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000017.10:g.3402354C>A
NC_000017.11:g.3499060C>A
NM_000049.3:c.914C>A NP_000040.1:p.Ala305Glu missense
... more HGVS
Protein change
A305E
Other names
914C-A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00040 (A)

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00016
Trans-Omics for Precision Medicine (TOPMed) 0.00018
1000 Genomes Project 0.00040
Exome Aggregation Consortium (ExAC) 0.00023
Links
UniProtKB: P45381#VAR_005001
OMIM: 608034.0003
dbSNP: rs28940574
ClinGen: CA252356
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 7 criteria provided, multiple submitters, no conflicts Feb 22, 2019 RCV000002725.9
Pathogenic 2 criteria provided, multiple submitters, no conflicts Apr 7, 2017 RCV000489986.2
Pathogenic 1 criteria provided, single submitter Mar 23, 2017 RCV000588914.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
ASPA - - GRCh38
GRCh37
3 133
SPATA22 - - GRCh38
GRCh37
- 203

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Apr 07, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000577185.3
Submitted: (Nov 28, 2017)
Evidence details
Comment:
The A305E missense variant has been reported in association with Canavan disease (Kaul et al., 1994;Kaul et al., 1996). The A305E variant accounts for 20-60% ... (more)
Pathogenic
(Jun 06, 2015)
criteria provided, single submitter
Method: clinical testing
Spongy degeneration of central nervous system
Allele origin: unknown
Counsyl
Accession: SCV000678170.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (4)
Pathogenic
(Mar 23, 2017)
criteria provided, single submitter
Method: clinical testing
Canavan Disease, Familial Form
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000694159.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (1)
Comment:
Variant summary: The ASPA c.914C>A (p.Ala305Glu) variant involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPs&GO not captured due to low ... (more)
Pathogenic
(Jul 14, 2014)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000231464.5
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
Pathogenic
(Nov 29, 2018)
criteria provided, single submitter
Method: clinical testing
Spongy degeneration of central nervous system
Allele origin: germline
Invitae
Accession: SCV000544590.3
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (2)
Comment:
This sequence change replaces alanine with glutamic acid at codon 305 of the ASPA protein (p.Ala305Glu). The alanine residue is highly conserved and there is ... (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Spongy degeneration of central nervous system
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894114.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Jan 26, 2018)
criteria provided, single submitter
Method: clinical testing
Spongy degeneration of central nervous system
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000914762.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (8)
Comment:
The ASPA c.914C>A (p.Ala305Glu) variant is frequently reported in non-Jewish individuals with Canavan disease (CD). Across a selection of the available literature, the p.Ala305Glu variant ... (more)
Pathogenic
(Feb 22, 2019)
criteria provided, single submitter
Method: clinical testing
CANAVAN DISEASE
Allele origin: germline
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996252.1
Submitted: (Sep 20, 2019)
Evidence details
Comment:
This established pathogenic variant has been previously reported as a homozygous and compound heterozygous change in patients with Canavan Disease (PMID: 20301412, 8023850, 10909858). Experimental ... (more)
Pathogenic
(Sep 01, 1995)
no assertion criteria provided
Method: literature only
CANAVAN DISEASE
Allele origin: germline
OMIM
Accession: SCV000022883.1
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (2)
Pathogenic
(Oct 03, 2015)
no assertion criteria provided
Method: research
Spongy degeneration of central nervous system
Allele origin: germline
Division of Human Genetics,Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536877.1
Submitted: (Jan 23, 2017)
Evidence details
Publications
PubMed (5)

Citations for this variant

Title Author Journal Year Link
Cytotoxic edema and diffusion restriction as an early pathoradiologic marker in canavan disease: case report and review of the literature. Merrill ST Orphanet journal of rare diseases 2016 PMID: 27927234
Atypical clinical and radiological course of a patient with Canavan disease. Sarret C Metabolic brain disease 2016 PMID: 26586007
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
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
Expression of aspartoacylase (ASPA) and Canavan disease. Sommer A Gene 2012 PMID: 22750302
Carrier testing for severe childhood recessive diseases by next-generation sequencing. Bell CJ Science translational medicine 2011 PMID: 21228398
Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Janson CG Annals of neurology 2006 PMID: 16437572
Atypical MRI findings in Canavan disease: a patient with a mild course. Yalcinkaya C Neuropediatrics 2005 PMID: 16217711
The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Shaag A American journal of human genetics 1995 PMID: 7668285
Canavan disease: mutations among Jewish and non-Jewish patients. Kaul R American journal of human genetics 1994 PMID: 8023850
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ASPA - - - -

Record last updated Oct 27, 2019