ClinVar Genomic variation as it relates to human health
NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000501.4(ELN):c.1621C>T (p.Arg541Ter)
Variation ID: 16723 Accession: VCV000016723.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.23 7: 74060184 (GRCh38) [ NCBI UCSC ] 7: 73474514 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 20, 2023 Nov 15, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000501.4:c.1621C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000492.2:p.Arg541Ter nonsense NM_001081752.3:c.1534C>T NP_001075221.1:p.Arg512Ter nonsense NM_001081753.3:c.1579C>T NP_001075222.1:p.Arg527Ter nonsense NM_001081754.3:c.1636C>T NP_001075223.1:p.Arg546Ter nonsense NM_001081755.3:c.1564C>T NP_001075224.1:p.Arg522Ter nonsense NM_001278912.2:c.1621C>T NP_001265841.1:p.Arg541Ter nonsense NM_001278913.2:c.1378C>T NP_001265842.1:p.Arg460Ter nonsense NM_001278914.2:c.1549C>T NP_001265843.1:p.Arg517Ter nonsense NM_001278915.2:c.1639C>T NP_001265844.1:p.Arg547Ter nonsense NM_001278916.2:c.1477+137C>T intron variant NM_001278917.2:c.1591C>T NP_001265846.1:p.Arg531Ter nonsense NM_001278918.2:c.1354C>T NP_001265847.1:p.Arg452Ter nonsense NM_001278939.2:c.1708C>T NP_001265868.1:p.Arg570Ter nonsense NC_000007.14:g.74060184C>T NC_000007.13:g.73474514C>T NG_009261.1:g.37088C>T - Protein change
- R570*, R452*, R460*, R512*, R517*, R522*, R527*, R531*, R541*, R546*, R547*
- Other names
- p.R541*:CGA>TGA
- 1621C-T
- Canonical SPDI
- NC_000007.14:74060183:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on RNA splicing Variation Ontology [VariO:0362]
- PubMed: 18348261
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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ELN | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
808 | 1123 | |
ELN-AS1 | - | - | - | GRCh38 | - | 223 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Nov 15, 2023 | RCV000018207.29 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 15, 2008 | RCV000018221.28 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 1, 2017 | RCV000198624.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2022 | RCV003390688.4 |
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
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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
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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
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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. |
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Pathogenic
(Sep 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000250046.14
First in ClinVar: Oct 11, 2015 Last updated: Dec 19, 2017 |
Comment:
The c.1621C>T variant in the ELN gene has been reported previously in one newborn with severe cutis laxa, congenital pulmonary disease, supravalvular pulmonary artery stenosis, … (more)
The c.1621C>T variant in the ELN gene has been reported previously in one newborn with severe cutis laxa, congenital pulmonary disease, supravalvular pulmonary artery stenosis, unilateral inguinal hernia and dysmorphic facial features (Graul-Neumann et al., 2008). The c.1621C>T variant alters the last (3') nucleotide of exon 24. mRNA studies using skin fibroblasts from the proband suggested that the variant abolished splicing from this exon/intron junction, resulting in in-frame skipping of this exon and expression of a protein lacking amino acids 526-540. The c.1621C>T variant was also present in this individual's unaffected father. However, expression studies using skin fibroblasts from the father showed that he had reduced expression of ELN mRNA, consistent with nonsense-mediated mRNA decay due to introduction of the R541X premature termination codon. The bases of this premature termination codon flank the intron and would only be present in an mRNA species that was spliced appropriately. The authors hypothesized that this potential difference in mRNA processing between father and son, while unexplained on a molecular/cellular level, may explain the highly variable clinical picture observed in this family (Graul- Neumann et al., 2008). The R541X variant has also been reported in association with supravalvular aortic stenosis (SVAS) in the absence of cutis laxa (reported as R570X in an alternate transcript of the ELN gene [Metcalfe et al., 2000; Li et al., 1997]). Metcalfe et al. reported R570X in one individual with sporadic, severe SVAS, peripheral pulmonary artery stenosis and bilateral inguinal hernias. Li et al. reported R570X in an individual with sporadic SVAS, and it was absent in >375 control samples. Functional studies were not performed in these cases. Other nonsense and splice site variants in the ELN gene have been reported in association with SVAS and cutis laxa. Furthermore, the c.1621C>T variants was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.1621 C>T in the ELN gene is interpreted as a disease-causing variant (less)
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Pathogenic
(Feb 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Supravalvar aortic stenosis
Affected status: yes
Allele origin:
germline
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Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739478.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: male
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
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Pathogenic
(Nov 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Supravalvar aortic stenosis
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV004102628.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Clinical Features:
Patent foramen ovale (present) , Aortic regurgitation (present) , Abnormal aortic morphology (present) , Coarctation of aorta (present) , Left ventricular hypertrophy (present) , Short … (more)
Patent foramen ovale (present) , Aortic regurgitation (present) , Abnormal aortic morphology (present) , Coarctation of aorta (present) , Left ventricular hypertrophy (present) , Short stature (present) , Supravalvar aortic stenosis (present) (less)
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Pathogenic
(Oct 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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ELN-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119759.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ELN c.1621C>T variant is predicted to result in premature protein termination (p.Arg541*). In an alternate transcript (NM_00127893.2) this variant is referred to as c.1708C>T … (more)
The ELN c.1621C>T variant is predicted to result in premature protein termination (p.Arg541*). In an alternate transcript (NM_00127893.2) this variant is referred to as c.1708C>T (p.Arg570*). This variant has been reported in multiple individuals with ELN-related disease and in at least one individual it was reported to occur de novo (see for example - Li et al. 1997. PubMed ID: 9215670; Table S9 - Jin et al. 2017. PubMed ID: 28991257). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in ELN are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Dec 01, 2000)
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no assertion criteria provided
Method: literature only
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SUPRAVALVULAR AORTIC STENOSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038486.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a sporadic case of SVAS (185500), Li et al. (1997) found a nonsense mutation: a C-to-T transition at nucleotide 1708, resulting in conversion of … (more)
In a sporadic case of SVAS (185500), Li et al. (1997) found a nonsense mutation: a C-to-T transition at nucleotide 1708, resulting in conversion of arginine-570 to a premature stop codon in exon 25 (R570X). DNA samples could not be obtained from the parents of the proband. Metcalfe et al. (2000) detected the R570X mutation in a sporadic case of SVAS with peripheral pulmonary artery stenosis and bilateral inguinal hernias. (less)
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Pathogenic
(Apr 15, 2008)
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no assertion criteria provided
Method: literature only
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CUTIS LAXA, AUTOSOMAL DOMINANT 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038500.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 13, 2020 |
Comment on evidence:
In a boy with severe cutis laxa (123700), severe congenital pulmonary disease (previously not reported in ADCL), and supravalvular pulmonary artery stenosis, Graul-Neumann et al. … (more)
In a boy with severe cutis laxa (123700), severe congenital pulmonary disease (previously not reported in ADCL), and supravalvular pulmonary artery stenosis, Graul-Neumann et al. (2008) identified a heterozygous 1621C-T transition in the ELN gene, resulting in an in-frame deletion of exon 25 and predicting a protein lacking amino acids 527-540. The same mutation was present in the clinically healthy father, but not in the mother, the paternal grandparents, or 96 healthy controls. Analysis of ELN expression in fibroblasts revealed the same amount of complete ELN mRNA in the proband as in normal age-matched controls, whereas the father had a more than 50% reduction of ELN mRNA expression as compared to corresponding age-matched controls. In contrast, addition of the translation inhibitor puromcin caused an increase in total ELN mRNA expression in the father. Graul-Neumann et al. (2008) concluded that the variable processing of an identically mutated gene (dominant negative in the child and haploinsufficiency in the father) caused the highly variable clinical appearance of ADCL in this family. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Highly variable cutis laxa resulting from a dominant splicing mutation of the elastin gene. | Graul-Neumann LM | American journal of medical genetics. Part A | 2008 | PMID: 18348261 |
Elastin: mutational spectrum in supravalvular aortic stenosis. | Metcalfe K | European journal of human genetics : EJHG | 2000 | PMID: 11175284 |
Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. | Li DY | Human molecular genetics | 1997 | PMID: 9215670 |
Text-mined citations for rs137854453 ...
HelpRecord last updated Mar 11, 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.