NM_000049.4(ASPA):c.634+1G>T AND Spongy degeneration of central nervous system

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Oct 7, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000666161.29

Allele description [Variation Report for NM_000049.4(ASPA):c.634+1G>T]

NM_000049.4(ASPA):c.634+1G>T

Genes:

ASPA:aspartoacylase [Gene - OMIM - HGNC]
SPATA22:spermatogenesis associated 22 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_000049.4(ASPA):c.634+1G>T

HGVS:

NC_000017.11:g.3489343G>T
NG_008399.2:g.20698G>T
NG_008399.3:g.20235G>T
NM_000049.4:c.634+1G>TMANE SELECT
NM_001128085.1:c.634+1G>T
NM_001321336.2:c.-73-19945C>A
NM_001321337.2:c.-73-19945C>A
NC_000017.10:g.3392637G>T
NM_000049.2:c.634+1G>T
NM_000049.2:c.[634+1G>T]

Links:

dbSNP: rs753871454

NCBI 1000 Genomes Browser:

rs753871454

Molecular consequence:

NM_001321336.2:c.-73-19945C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001321337.2:c.-73-19945C>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000049.4:c.634+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001128085.1:c.634+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Spongy degeneration of central nervous system
Synonyms:: Canavan disease; Canavan-van Bogaert-Bertrand disease; Spongy degeneration of the central nervous system; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010079; MedGen: C0206307; Orphanet: 141; OMIM: 271900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914760	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Dec 5, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18978679, 10701101, 19685155 Citation Link,
SCV001250604	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	no assertion criteria provided	Uncertain significance	inherited	clinical testing
SCV001591755	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 7, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16199547, 12638939, 10701101, 16854607, 18978679, 28492532
SCV002033129	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002060241	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Nov 8, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10701101, 33547378 Citation Link,
SCV002072985	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002093206	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 17, 2017)	germline	clinical testing
SCV004201904	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.

Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grunberg NE, Gahl WA, Namboodiri AMA.

J Inherit Metab Dis. 2009 Oct;32(5):640. doi: 10.1007/s10545-009-1155-3. Epub 2009 Aug 15.

PubMed [citation]

PMID:: 19685155

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (9)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914760.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The ASPA c.634+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.634+1G>T variant has been reported in three studies and is found in a homozygous state in three unrelated probands (Rady et al. 2000; Kaya et al. 2008; Madhavarao et al. 2009). The probands were all clinically diagnosed with Canavan disease and have variable phenotypic expressivity. The variant was also identified in a heterozygous state in the unaffected parents and an unaffected sibling of one of the probands (Rady et al. 2000). Control data are unavailable for this variant, which is reported at a frequency of 0.000011 in the Total population from the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, the c.634+1G>T variant is classified as likely pathogenic for Canavan disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,, SCV001250604.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001591755.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change affects a donor splice site in intron 4 of the ASPA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ASPA are known to be pathogenic (PMID: 12638939). This variant is present in population databases (rs753871454, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with Canavan disease (PMID: 10701101, 16854607, 18978679). ClinVar contains an entry for this variant (Variation ID: 551174). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002033129.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV002060241.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

NM_000049.2(ASPA):c.634+1G>T is a canonical splice variant classified as pathogenic in the context of Canavan disease. c.634+1G>T has been observed in cases with relevant disease (PMID: 10701101, 33547378). Functional assessments of this variant are not available in the literature. c.634+1G>T has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000049.2(ASPA):c.634+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV002072985.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The splice donor variant c.634+1G>T in ASPA (NM_000049.4) has been reported previously in affected patients (Rady et al, 2000; Kaya et al, 2008; Madhavarao et al, 2009). It has been submitted to ClinVar as Pathogenic. The c.634+1G>T variant is observed in 1/30,538 (0.0033%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The variant affects an invariant splice nucleotide and is predicted to cause loss of function. Loss of function variants have been reported to be disease causing in ASPA gene. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002093206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201904.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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