NM_000049.2(ASPA):c.693C>A (p.Tyr231Ter) AND Spongy degeneration of central nervous system

Clinical significance:Pathogenic (Last evaluated: Jun 14, 2016)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000002727.5

Allele description

NM_000049.2(ASPA):c.693C>A (p.Tyr231Ter)

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_000049.2(ASPA):c.693C>A (p.Tyr231Ter)
HGVS:
  • NC_000017.11:g.3494408C>A
  • NG_008399.1:g.25299C>A
  • NM_000049.2:c.693C>A
  • NM_001128085.1:c.693C>A
  • NP_000040.1:p.Tyr231Ter
  • NP_001121557.1:p.Tyr231Ter
  • NC_000017.10:g.3397702C>A
Protein change:
Y231*; TYR231TER
Links:
OMIM: 608034.0005; dbSNP: rs12948217
GMAF:
0.2037(T), 12948217
NCBI 1000 Genomes Browser:
rs12948217
Molecular consequence:
  • NM_001128085.1:c.693C>A - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

Condition(s)

Name:
Spongy degeneration of central nervous system
Identifiers:
MedGen: C0206307; Orphanet: 141; OMIM: 271900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000022885OMIMno assertion criteria providedPathogenic
(Nov 1, 1998)
germlineliterature only

PubMed (3)
[See all records that cite these PMIDs]

SCV000230836EGL Genetic Diagnostics,Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Jul 14, 2014)
germlineclinical testing

Citation Link,

SCV000245579Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine - CSER-MedSeqcriteria provided, single submitter
Pathogenic
(Oct 20, 2014)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000262467Invitaecriteria provided, single submitter
Pathogenic
(Apr 7, 2016)
germlineclinical testing

Citation Link,

SCV000402018Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Jun 14, 2016)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedliterature only, clinical testing

Citations

PubMed

Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.

Kaul R, Balamurugan K, Gao GP, Matalon R.

Genomics. 1994 May 15;21(2):364-70.

PubMed [citation]
PMID:
8088831

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000022885.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

In Ashkenazi Jewish patients with Canavan disease (271900), Kaul et al. (1994) identified a 693C-A nonsense mutation in exon 5 of the ASPA gene (Y231X). They also identified a silent polymorphism, 693C/T. Expression of the mutation in COS-1 cells showed a complete loss of ASPA enzyme activity.

Among Ashkenazi Jewish patients with Canavan disease, Kaul et al. (1996) found that the G285A missense mutation (608034.0001) and the Y231X nonsense mutation accounted for 97% of 104 mutant chromosomes examined.

Propheta et al. (1998) found a sequence polymorphism at nucleotide 693 (693C/T); the relative frequency of the 693C and the 693T alleles in the tested population was 0.75 and 0.25, respectively. The practical significance was that the 693T allele yielded results like those of the 693A mutation in some test systems.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, SCV000230836.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine - CSER-MedSeq, SCV000245579.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The p.Tyr231X variant in ASPA has been reported in numerous individuals with Canavan disease (Kaul 1994) and is one of the most common disease-causing ASPA variants in the Ashkenazi Jewish population. It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 231 which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for Canavan disease in an autosomal recessive manner.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Invitae, SCV000262467.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This sequence change creates a premature translational stop signal at codon 231 (p.Tyr231*) of the ASPA gene. It is expected to result in an absent or disrupted protein product. This variant is clearly defined as a Canavan disease causative allele (PMID: 8023850, 8659549, 10909858). It is a common cause of Canavan disease in individuals of Ashkenazi Jewish ancestry. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000402018.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The c.693C>A (p.Tyr231Ter) variant is a stop-gained variant and is predicted to to result in premature termination of the protein. The variant has been reported in two studies and is found in a total of 13 Canavan disease patients including one homozygote and 12 compound heterozygotes (Kaul et al. 1994; Kaul et al. 1996). Twelve of the patients were of Ashkenazi Jewish descent. Control data are unavailable for this variant, which is reported at a frequency of 0.00011 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Kaul et al. (1994) demonstrated a complete loss of ASPA activity when the p.Tyr231Ter variant was expressed in COS-1 cells. Based on the collective evidence and potential impact of stop-gained variants, the p.Tyr231Ter variant is classified as pathogenic for Canavan disease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 27, 2017

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