NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168C has been observed in cases with relevant disease (PMID: 27531131, 16854607, 8659549, 28101991). Functional assessments of this variant are available in the literature (PMID: 8659549). Internal structural analysis of the variant is supportive of pathogenicity. R168C has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant that has both functional and internal structural support for pathogenicity and 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.
ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.502C>T (p.Arg168Cys)
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.502C>T (p.Arg168Cys)
Variation ID: 813438 Accession: VCV000813438.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.2 17: 3483568 (GRCh38) [ NCBI UCSC ] 17: 3386862 (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 Feb 29, 2020 Oct 20, 2024 Nov 2, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000049.4:c.502C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Arg168Cys missense NM_000049.2:c.502C>T NM_001128085.1:c.502C>T NP_001121557.1:p.Arg168Cys missense NM_001321336.2:c.-73-14170G>A intron variant NM_001321337.2:c.-73-14170G>A intron variant NC_000017.11:g.3483568C>T NC_000017.10:g.3386862C>T NG_008399.2:g.14923C>T NG_008399.3:g.14460C>T - Protein change
- R168C
- Other names
- -
- Canonical SPDI
- NC_000017.11:3483567:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00000
- 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 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 2, 2023 | RCV001004409.20 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2019 | RCV001093137.27 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2021 | RCV002551712.9 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163412.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
|
|
|
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: SCV002032873.1
First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
|
|
Likely pathogenic
(Nov 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060037.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168C has been observed in cases with relevant disease (PMID: … (more)
NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168C has been observed in cases with relevant disease (PMID: 27531131, 16854607, 8659549, 28101991). Functional assessments of this variant are available in the literature (PMID: 8659549). Internal structural analysis of the variant is supportive of pathogenicity. R168C has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant that has both functional and internal structural support for pathogenicity and 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. (less)
|
|
|
Likely pathogenic
(Aug 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002780125.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Nov 02, 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: SCV001575909.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the ASPA protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the ASPA protein (p.Arg168Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Canavan disease (PMID: 8659549, 16854607; Invitae). ClinVar contains an entry for this variant (Variation ID: 813438). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). This variant disrupts the p.Arg168 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909858, 28101991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003582170.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.502C>T (p.R168C) alteration is located in exon 3 (coding exon 3) of the ASPA gene. This alteration results from a C to T substitution … (more)
The c.502C>T (p.R168C) alteration is located in exon 3 (coding exon 3) of the ASPA gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in patients with Canavan disease (Kaul, 1996; Zeng, 2006; Zaki, 2017). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located at a position and in a region critical for protein function (Wijayasinghe, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249972.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the ASPA protein (p.Arg168Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Canavan disease (PMID: 8659549, 16854607; Invitae). ClinVar contains an entry for this variant (Variation ID: 813438). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). This variant disrupts the p.Arg168 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909858, 28101991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.502C>T (p.R168C) alteration is located in exon 3 (coding exon 3) of the ASPA gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in patients with Canavan disease (Kaul, 1996; Zeng, 2006; Zaki, 2017). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located at a position and in a region critical for protein function (Wijayasinghe, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely 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:
NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant classified as likely pathogenic in the context of Canavan disease. R168C has been observed in cases with relevant disease (PMID: 27531131, 16854607, 8659549, 28101991). Functional assessments of this variant are available in the literature (PMID: 8659549). Internal structural analysis of the variant is supportive of pathogenicity. R168C has been observed in population frequency databases (gnomAD: FIN 0.005%). In summary, NM_000049.2(ASPA):c.502C>T(R168C) is a missense variant that has both functional and internal structural support for pathogenicity and 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.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the ASPA protein (p.Arg168Cys). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with Canavan disease (PMID: 8659549, 16854607; Invitae). ClinVar contains an entry for this variant (Variation ID: 813438). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ASPA protein function. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). This variant disrupts the p.Arg168 amino acid residue in ASPA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909858, 28101991). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.502C>T (p.R168C) alteration is located in exon 3 (coding exon 3) of the ASPA gene. This alteration results from a C to T substitution at nucleotide position 502, causing the arginine (R) at amino acid position 168 to be replaced by a cysteine (C). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in patients with Canavan disease (Kaul, 1996; Zeng, 2006; Zaki, 2017). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located at a position and in a region critical for protein function (Wijayasinghe, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity. | Mendes MI | Human mutation | 2017 | PMID: 28101991 |
| Two patients with Canavan disease and structural modeling of a novel mutation. | Zaki OK | Metabolic brain disease | 2017 | PMID: 27531131 |
| Aspartoacylase catalytic deficiency as the cause of Canavan disease: a structural perspective. | Wijayasinghe YS | Biochemistry | 2014 | PMID: 25003821 |
| 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 |
| Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population. | Sistermans EA | European journal of human genetics : EJHG | 2000 | PMID: 10909858 |
| Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. | Kaul R | American journal of human genetics | 1996 | PMID: 8659549 |
Text-mined citations for rs937670540 ...
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 03, 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.