This sequence change creates a premature translational stop signal (p.Trp581*) in the ARSE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the ARSE protein. This variant is present in population databases (rs80338714, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with chondrodysplasia punctata (PMID: 9863597, 12567415). ClinVar contains an entry for this variant (Variation ID: 11529). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000047.3(ARSL):c.1743G>A (p.Trp581Ter)
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.
(12)
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
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000047.3(ARSL):c.1743G>A (p.Trp581Ter)
Variation ID: 11529 Accession: VCV000011529.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp22.33 X: 2934859 (GRCh38) [ NCBI UCSC ] X: 2852900 (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 Apr 4, 2013 Sep 16, 2024 Sep 4, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000047.3:c.1743G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000038.2:p.Trp581Ter nonsense NM_001282628.2:c.1818G>A NP_001269557.1:p.Trp606Ter nonsense NM_001282631.2:c.1581G>A NP_001269560.2:p.Trp527Ter nonsense NM_001369079.1:c.1770G>A NP_001356008.1:p.Trp590Ter nonsense NM_001369080.1:c.1818G>A NP_001356009.1:p.Trp606Ter nonsense NC_000023.11:g.2934859C>T NC_000023.10:g.2852900C>T NG_007091.1:g.34412G>A - Protein change
- W581*, W590*, W527*, W606*
- Other names
-
W581X
- Canonical SPDI
- NC_000023.11:2934858: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.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
- 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. |
|||
| ARSL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
428 | 668 | |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
May 23, 2024 | RCV000012285.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 4, 2024 | RCV000485780.7 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 18, 2020 | RCV001196991.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 3, 2024 | RCV002512981.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 30, 2024 | RCV004658960.1 |
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 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018874.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Chondrodysplasia punctata, brachytelephalangic, autosomal
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003516459.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp581*) in the ARSE gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Trp581*) in the ARSE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the ARSE protein. This variant is present in population databases (rs80338714, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with chondrodysplasia punctata (PMID: 9863597, 12567415). ClinVar contains an entry for this variant (Variation ID: 11529). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002587080.2
First in ClinVar: Oct 29, 2022 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PVS1_MOD, PS4, PM2_SUP
Clinical Features:
Neurodegeneration (present) , Autism (present) , Cerebellar ataxia (present) , Peripheral neuropathy (present) , Profound global developmental delay (present) , Abnormal circulating creatine concentration (present)
Sex: male
|
|
|
Likely pathogenic
(May 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005090977.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
Comment:
PVS1, PM2, PP5-The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported … (more)
PVS1, PM2, PP5-The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 11529). It has been previously reported as causative for chondrodysplasia punctata (PMID: 9863597, 12567415) (less)
|
|
|
Pathogenic
(Sep 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000564593.9
First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation as the last 9 amino acids are lost, although loss-of-function variants have not been reported downstream of … (more)
Nonsense variant predicted to result in protein truncation as the last 9 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 9863597, 34529350, 32860008, 19839041, 30084160, 12567415, 26526591) (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426469.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
|
|
|
Likely pathogenic
(Feb 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367626.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Clinical Features:
Renal dysplasia (present) , Global developmental delay (present) , Coarctation of aorta (present) , Abnormal facial shape (present)
|
|
|
Pathogenic
(Nov 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
(X-linked recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004171252.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Clinical Features:
Metaphyseal chondrodysplasia (present) , Hyperplasia of midface (present) , Hypoplastic nasal bone (present)
|
|
|
Pathogenic
(Apr 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005163663.1
First in ClinVar: Aug 11, 2024 Last updated: Aug 11, 2024 |
Comment:
The c.1743G>A (p.W581*) alteration, located in exon 11 (coding exon 10) of the ARSL gene, consists of a G to A substitution at nucleotide position … (more)
The c.1743G>A (p.W581*) alteration, located in exon 11 (coding exon 10) of the ARSL gene, consists of a G to A substitution at nucleotide position 1743. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 581. This alteration occurs at the 3' terminus of the ARSL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 1.5% of the protein. The exact functional effect of this alteration is unknown. Based on data from gnomAD, the c.1743G>A allele has an overall frequency of 0.001% (2/197636) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.002% (2/89531) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with ARSL-related chondrodysplasia punctata (Sheffield, 1998; Brunetti-Pierri, 2003; Mazzone, 2019; Bertoli-Avella, 2021). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 05, 2020)
|
no assertion criteria provided
Method: clinical testing
|
X-linked chondrodysplasia punctata 1
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190738.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
|
|
Pathogenic
(Mar 01, 2003)
|
no assertion criteria provided
Method: literature only
|
CHONDRODYSPLASIA PUNCTATA 1, X-LINKED RECESSIVE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000032519.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
In 4 unrelated patients with chondrodysplasia punctata (CDPX1; 302950), Brunetti-Pierri et al. (2003) identified a 2045G-A transition in exon 10 of the ARSE gene, resulting … (more)
In 4 unrelated patients with chondrodysplasia punctata (CDPX1; 302950), Brunetti-Pierri et al. (2003) identified a 2045G-A transition in exon 10 of the ARSE gene, resulting in a trp581-to-ter (W581X) substitution. The authors noted that the W581X mutation seemed to be the most prevalent among patients with identified mutations of the ARSE gene. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
X-linked chondrodysplasia punctata 1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040399.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Criteria applied: PVS1_MOD, PS4, PM2_SUP
Comment:
PVS1, PM2, PP5-The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 11529). It has been previously reported as causative for chondrodysplasia punctata (PMID: 9863597, 12567415)
Comment:
Nonsense variant predicted to result in protein truncation as the last 9 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 9863597, 34529350, 32860008, 19839041, 30084160, 12567415, 26526591)
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Comment:
The c.1743G>A (p.W581*) alteration, located in exon 11 (coding exon 10) of the ARSL gene, consists of a G to A substitution at nucleotide position 1743. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 581. This alteration occurs at the 3' terminus of the ARSL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 1.5% of the protein. The exact functional effect of this alteration is unknown. Based on data from gnomAD, the c.1743G>A allele has an overall frequency of 0.001% (2/197636) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.002% (2/89531) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with ARSL-related chondrodysplasia punctata (Sheffield, 1998; Brunetti-Pierri, 2003; Mazzone, 2019; Bertoli-Avella, 2021). Based on the available evidence, this alteration 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:
This sequence change creates a premature translational stop signal (p.Trp581*) in the ARSE gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the ARSE protein. This variant is present in population databases (rs80338714, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with chondrodysplasia punctata (PMID: 9863597, 12567415). ClinVar contains an entry for this variant (Variation ID: 11529). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PVS1_MOD, PS4, PM2_SUP
Comment:
PVS1, PM2, PP5-The variant is expected to result in an absent or disrupted protein product. Low frequency in gnomAD population databases. It has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 11529). It has been previously reported as causative for chondrodysplasia punctata (PMID: 9863597, 12567415)
Comment:
Nonsense variant predicted to result in protein truncation as the last 9 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 9863597, 34529350, 32860008, 19839041, 30084160, 12567415, 26526591)
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Comment:
The c.1743G>A (p.W581*) alteration, located in exon 11 (coding exon 10) of the ARSL gene, consists of a G to A substitution at nucleotide position 1743. This changes the amino acid from a tryptophan (W) to a stop codon at amino acid position 581. This alteration occurs at the 3' terminus of the ARSL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 1.5% of the protein. The exact functional effect of this alteration is unknown. Based on data from gnomAD, the c.1743G>A allele has an overall frequency of 0.001% (2/197636) total alleles studied, with 1 hemizygote observed. The highest observed frequency was 0.002% (2/89531) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with ARSL-related chondrodysplasia punctata (Sheffield, 1998; Brunetti-Pierri, 2003; Mazzone, 2019; Bertoli-Avella, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Chondrodysplasia Punctata 1, X-Linked. | Adam MP | - | 2020 | PMID: 20301713 |
| Binder syndrome: a phenotype rather than a definitive diagnosis? | Mazzone E | Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology | 2019 | PMID: 30084160 |
| X-linked recessive chondrodysplasia punctata: spectrum of arylsulfatase E gene mutations and expanded clinical variability. | Brunetti-Pierri N | American journal of medical genetics. Part A | 2003 | PMID: 12567415 |
| Segregation of mutations in arylsulphatase E and correlation with the clinical presentation of chondrodysplasia punctata. | Sheffield LJ | Journal of medical genetics | 1998 | PMID: 9863597 |
Text-mined citations for rs80338714 ...
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 Sep 29, 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.