The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 374305; PMID: 23236030) - PS4_moderate. The variant is present at low allele frequencies population databases (rs149459910 – gnomAD 0.01117%; ABraOM no frequency- http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp490*) was detected in trans with a pathogenic variant (PMID: 23236030) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
ClinVar Genomic variation as it relates to human health
NM_004826.4(ECEL1):c.1470G>A (p.Trp490Ter)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004826.4(ECEL1):c.1470G>A (p.Trp490Ter)
Variation ID: 374305 Accession: VCV000374305.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.1 2: 232483452 (GRCh38) [ NCBI UCSC ] 2: 233348162 (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 Jan 13, 2017 Apr 6, 2024 Mar 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004826.4:c.1470G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004817.2:p.Trp490Ter nonsense NM_001290787.2:c.1470G>A NP_001277716.1:p.Trp490Ter nonsense NC_000002.12:g.232483452C>T NC_000002.11:g.233348162C>T NG_034065.1:g.9408G>A - Protein change
- W490*
- Other names
- -
- Canonical SPDI
- NC_000002.12:232483451: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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00011
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00021
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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. |
|||
| ECEL1 | - | - |
GRCh38 GRCh37 |
217 | 260 | |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000414781.14 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Sep 9, 2022 | RCV000627254.6 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 11, 2019 | RCV002252117.2 |
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
|
Distal arthrogryposis type 5D
Affected status: yes
Allele origin:
germline
|
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV001438953.1
First in ClinVar: Oct 25, 2020 Last updated: Oct 25, 2020 |
Number of individuals with the variant: 2
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
|
Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Distal arthrogryposis type 5D
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061226.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product … (more)
The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 374305; PMID: 23236030) - PS4_moderate. The variant is present at low allele frequencies population databases (rs149459910 – gnomAD 0.01117%; ABraOM no frequency- http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp490*) was detected in trans with a pathogenic variant (PMID: 23236030) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Jun 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523981.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PVS1, PM1, PP5, BS1
Clinical Features:
Scoliosis (present) , Patellar dislocation (present) , Narrow mouth (present) , Mitral valve prolapse (present) , Knee flexion contracture (present) , Joint laxity (present) , … (more)
Scoliosis (present) , Patellar dislocation (present) , Narrow mouth (present) , Mitral valve prolapse (present) , Knee flexion contracture (present) , Joint laxity (present) , Hernia (present) , Camptodactyly (present) , Blue sclerae (present) (less)
Geographic origin: Brazil
|
|
|
Pathogenic
(Sep 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000748246.4
First in ClinVar: May 21, 2018 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27959697, 33491998, 23236030, 30131190, 31127727, 33101984, 33672664) (less)
|
|
|
Pathogenic
(Sep 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Distal arthrogryposis type 5D
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003800057.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, … (more)
The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, Dieterich 2013, Posey 2017). This variant is found in the African/African-American population with an allele frequency of 0.048% (12/24910 alleles) in the Genome Aggregation Database ; it is also reported in ClinVar (Variation ID: 374305). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: AlBanji MH et al. Utility of Hypotonia Diagnostic Investigations: A 12-year Single Center Study. Mol Genet Metab Rep. 2020 Oct 21;25:100665. PMID: 33101984 Dieterich K et al. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet. 2013 Apr 15;22(8):1483-92. PMID: 23236030. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697 (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Distal arthrogryposis type 5D
Affected status: yes
Allele origin:
biparental
|
Molecular Genetics Lab, CHRU Brest
Accession: SCV004697614.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Distal arthrogryposis type 5D
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804950.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Sep 29, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Distal arthrogryposis type 5D
(Autosomal recessive inheritance)
Affected status: yes, unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000328781.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
Comment:
Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features … (more)
Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features of delayed motor milestones, dysmorphic features, joint contracture at elbow, knee and small joints and camptodactyly. Compound heterozygous pathogenic variants including c.1470G>A (p.W490X) have been previously reported in a patient with recessive form of distal arthrogryposis (PMID 23236030). Heterozygotes for this variant would be expected to be asymptomatic carriers. (less)
Observation 1:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Geographic origin: Middle East
Observation 2:
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Ethnicity/Population group: African American,Hispanic Americans
|
|
|
Pathogenic
(Feb 05, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Distal arthrogryposis type 5D
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190789.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807429.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951286.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
ACMG classification criteria: PVS1, PM1, PP5, BS1
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27959697, 33491998, 23236030, 30131190, 31127727, 33101984, 33672664)
Comment:
The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, Dieterich 2013, Posey 2017). This variant is found in the African/African-American population with an allele frequency of 0.048% (12/24910 alleles) in the Genome Aggregation Database ; it is also reported in ClinVar (Variation ID: 374305). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: AlBanji MH et al. Utility of Hypotonia Diagnostic Investigations: A 12-year Single Center Study. Mol Genet Metab Rep. 2020 Oct 21;25:100665. PMID: 33101984 Dieterich K et al. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet. 2013 Apr 15;22(8):1483-92. PMID: 23236030. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697
Comment:
Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features of delayed motor milestones, dysmorphic features, joint contracture at elbow, knee and small joints and camptodactyly. Compound heterozygous pathogenic variants including c.1470G>A (p.W490X) have been previously reported in a patient with recessive form of distal arthrogryposis (PMID 23236030). Heterozygotes for this variant would be expected to be asymptomatic carriers.
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:
The c.1470G>A;p.(Trp490*) variant creates a premature translational stop signal in the ECEL1 gene. It is expected to result in an absent or disrupted protein product - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 374305; PMID: 23236030) - PS4_moderate. The variant is present at low allele frequencies population databases (rs149459910 – gnomAD 0.01117%; ABraOM no frequency- http://abraom.ib.usp.br/) -PM2_supporting. The p.(Trp490*) was detected in trans with a pathogenic variant (PMID: 23236030) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG classification criteria: PVS1, PM1, PP5, BS1
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27959697, 33491998, 23236030, 30131190, 31127727, 33101984, 33672664)
Comment:
The ECEL1 c.1470G>A; p.Trp490Ter variant (rs149459910) is reported in the literature in the compound heterozygous and homozygous states in individuals with distal arthrogryposis (AlBanji 2020, Dieterich 2013, Posey 2017). This variant is found in the African/African-American population with an allele frequency of 0.048% (12/24910 alleles) in the Genome Aggregation Database ; it is also reported in ClinVar (Variation ID: 374305). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: AlBanji MH et al. Utility of Hypotonia Diagnostic Investigations: A 12-year Single Center Study. Mol Genet Metab Rep. 2020 Oct 21;25:100665. PMID: 33101984 Dieterich K et al. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. Hum Mol Genet. 2013 Apr 15;22(8):1483-92. PMID: 23236030. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697
Comment:
Our laboratory reported dual molecular diagnoses in ARHGEF10 (NM_014629.2, c.1456dup and c.2063G>A in trans) and ECEL1 (NM_004826.2, c.1470G>A) in this individual reported to have features of delayed motor milestones, dysmorphic features, joint contracture at elbow, knee and small joints and camptodactyly. Compound heterozygous pathogenic variants including c.1470G>A (p.W490X) have been previously reported in a patient with recessive form of distal arthrogryposis (PMID 23236030). Heterozygotes for this variant would be expected to be asymptomatic carriers.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis. | Dieterich K | Human molecular genetics | 2013 | PMID: 23236030 |
Text-mined citations for rs149459910 ...
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 Aug 04, 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.