This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
ClinVar Genomic variation as it relates to human health
NM_018255.4(ELP2):c.293dup (p.Leu98fs)
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.
(6)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_018255.4(ELP2):c.293dup (p.Leu98fs)
Variation ID: 1012186 Accession: VCV001012186.6
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 18q12.2 18: 36138270-36138271 (GRCh38) [ NCBI UCSC ] 18: 33718233-33718234 (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 Mar 7, 2021 Apr 20, 2024 Mar 19, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018255.4:c.293dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060725.1:p.Leu98fs frameshift NM_001242875.1:c.293dup NM_001242875.1:c.293dupT NM_001242875.3:c.293dup NP_001229804.1:p.Leu98fs frameshift NM_001242876.3:c.293dup NP_001229805.1:p.Leu98fs frameshift NM_001242877.3:c.293dup NP_001229806.1:p.Leu98fs frameshift NM_001242878.3:c.293dup NP_001229807.1:p.Leu98fs frameshift NM_001242879.3:c.293dup NP_001229808.1:p.Leu98fs frameshift NM_001324465.2:c.293dup NP_001311394.1:p.Leu98fs frameshift NM_001324466.2:c.293dup NP_001311395.1:p.Leu98fs frameshift NM_001324467.2:c.293dup NP_001311396.1:p.Leu98fs frameshift NM_001324468.2:c.-155dup 5 prime UTR NR_040110.3:n.328dup non-coding transcript variant NR_136897.2:n.328dup non-coding transcript variant NR_136898.2:n.328dup non-coding transcript variant NR_137173.2:n.328dup non-coding transcript variant NC_000018.10:g.36138274dup NC_000018.9:g.33718237dup NG_050745.1:g.13401dup - Protein change
- L98fs
- Other names
- -
- Canonical SPDI
- NC_000018.10:36138270:TTTT:TTTTT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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probably has functional consequence
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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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0.00060 (TTTTT)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| ELP2 | - | - |
GRCh38 GRCh37 |
153 | 203 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV001310088.1 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2023 | RCV001335775.3 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 19, 2024 | RCV003223717.3 |
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
(May 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal recessive 58
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001529008.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Uncertain significance
(Apr 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003919433.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more)
Frameshift 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; Has not been previously published as pathogenic or benign to our knowledge (less)
|
|
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Likely pathogenic
(Jun 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal recessive 58
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV004013354.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PVS1, PM3
|
|
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Likely pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Intellectual disability, autosomal recessive 58
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004101339.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss … (more)
The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder. (less)
|
|
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Uncertain Significance
(Mar 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847460.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 … (more)
The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1. (less)
|
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability, profound
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Wainwright Lab, University Of Queensland
Accession: SCV001482310.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Number of individuals with the variant: 2
Clinical Features:
Seizure (present) , Hypersomnia (present) , Limb dysmetria (present) , Absent speech (present) , Global developmental delay (present)
Sex: mixed
Comment on evidence:
A heterozygous frameshift variant in the ELP2 gene, NM_001242875.2:c.289_290insT, NP_001229804.1:p.Leu98Phefs. The two siblings have another variant in this gene (compound heterozygous), NM_001242875.2:c.1409C>T, NP_001229804.1:p.Thr470Ile.
|
Comment:
Comment:
Frameshift 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; Has not been previously published as pathogenic or benign to our knowledge
Comment:
PVS1, PM3
Comment:
The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder.
Comment:
The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
probably has functional consequence
|
Wainwright Lab, University Of Queensland
Accession: SCV001482310.1
|
|
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
Frameshift 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; Has not been previously published as pathogenic or benign to our knowledge
Comment:
PVS1, PM3
Comment:
The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder.
Comment:
The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1.
Citations for germline classification of this variant
Help| There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs529659464 ...
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 Jun 23, 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.