VCV000188803.39 - ClinVar

NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)

Germline

Classification

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)

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

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

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.2 17: 3499005 (GRCh38) [ NCBI UCSC ] 17: 3402299 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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

Nucleotide	Protein	Molecular consequence
NM_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_008399.3:g.29897G>A
	P45381:p.Ala287Thr

... more HGVS ... less HGVS

Protein change

A287T

Other names

Canonical SPDI

NC_000017.11:3499004:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA273981 UniProtKB: P45381#VAR_039090 dbSNP: rs774323189 VarSome

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
Gene	OMIM	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	21	593

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.
Spongy degeneration of central nervous system	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 5, 2024	RCV000169134.24
Canavan Disease, Familial Form	Pathogenic (1)	criteria provided, single submitter	Aug 4, 2016	RCV000587229.9
not provided	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 (May 24, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) 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	Publications: PubMed (7) PubMed: 23233226‚ 12638939‚ 10407784‚ 17194761‚ 22019069‚ 22878930‚ 16854607
Likely pathogenic (Jan 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) 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 (Nov 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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	Publications: PubMed (3) PubMed: 12638939‚ 16854607‚ 26992473 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)
Pathogenic (Jun 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) 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
Pathogenic (Aug 04, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) 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	Publications: PubMed (3) PubMed: 10407784‚ 22019069‚ 22878930 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 (ACMG Guidelines, 2015) 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
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:

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.

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.

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:

Citations for germline classification of this variant

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 ...

These 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 Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs774323189 ...