DNA sequence analysis of the ELOVL4 gene demonstrated a sequence change, c.698C>T, that results in an amino acid change, p.Thr233Met. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Thr233Met change has been described in one patient with a combination of erythrokeratodermia and spinocerebellar ataxia (SCA34) (PMID: 30065956). The p.Thr233Met change affects a moderately conserved amino acid residue located in a domain of the ELOVL4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr233Met substitution. Subsequent targeted sequence analysis revealed the absence of this sequence change in both parents. The p.Thr233Met sequence change in the ELOVL4 gene appears to be a de novo event in this individual. Based on the de novo and novel nature of this sequence change, we interpret it as likely pathogenic, however functional studies have not been performed to prove this conclusively.
ClinVar Genomic variation as it relates to human health
NM_022726.4(ELOVL4):c.698C>T (p.Thr233Met)
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.
Conflicting classifications of pathogenicity
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
Pathogenic(5); Likely pathogenic(1); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_022726.4(ELOVL4):c.698C>T (p.Thr233Met)
Variation ID: 547008 Accession: VCV000547008.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6q14.1 6: 79916855 (GRCh38) [ NCBI UCSC ] 6: 80626572 (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 Jul 9, 2018 Oct 20, 2024 Jul 18, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_022726.4:c.698C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_073563.1:p.Thr233Met missense NC_000006.12:g.79916855G>A NC_000006.11:g.80626572G>A NG_009108.2:g.35744C>T - Protein change
- T233M
- Other names
- -
- Canonical SPDI
- NC_000006.12:79916854:G:A
-
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.
- -
- 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. |
|||
| ELOVL4 | - | - |
GRCh38 GRCh37 |
314 | 333 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 18, 2024 | RCV000659060.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 18, 2024 | RCV001809734.4 | |
|
ELOVL4-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Feb 7, 2024 | RCV003994070.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001905602.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Clinical Features:
Cerebellar ataxia (present)
Sex: male
|
|
|
Likely pathogenic
(Nov 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064418.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ELOVL4 gene demonstrated a sequence change, c.698C>T, that results in an amino acid change, p.Thr233Met. This sequence change has not … (more)
DNA sequence analysis of the ELOVL4 gene demonstrated a sequence change, c.698C>T, that results in an amino acid change, p.Thr233Met. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Thr233Met change has been described in one patient with a combination of erythrokeratodermia and spinocerebellar ataxia (SCA34) (PMID: 30065956). The p.Thr233Met change affects a moderately conserved amino acid residue located in a domain of the ELOVL4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr233Met substitution. Subsequent targeted sequence analysis revealed the absence of this sequence change in both parents. The p.Thr233Met sequence change in the ELOVL4 gene appears to be a de novo event in this individual. Based on the de novo and novel nature of this sequence change, we interpret it as likely pathogenic, however functional studies have not been performed to prove this conclusively. (less)
|
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933753.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 233 of the ELOVL4 protein (p.Thr233Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 233 of the ELOVL4 protein (p.Thr233Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spinocerebellar ataxia (PMID: 30065956, 31105016, 34234304, 34623043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 547008). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ELOVL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
ELOVL4-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813241.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: ELOVL4 c.698C>T (p.Thr233Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: ELOVL4 c.698C>T (p.Thr233Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251008 control chromosomes (gnomAD). c.698C>T has been reported in the literature in multiple individuals affected with erythrokeratodermia and spinocerebellar ataxia 34 (examples: Bourque_2018, Ozaki_2019, Benkirane_2021, and Wang_2021). The variant segregated with the disease in multiple families. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30065956, 34234304, 34623043, 31105016). ClinVar contains an entry for this variant (Variation ID: 547008). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Spinocerebellar ataxia type 34
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059733.2
First in ClinVar: Jan 15, 2022 Last updated: Sep 08, 2024 |
|
|
|
Pathogenic
(Nov 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001782107.4
First in ClinVar: Aug 14, 2021 Last updated: Oct 08, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30065956, 34623043, 33816655, 33556440, 33655653, 34234304, 31105016, 36696030, 36464075) (less)
|
|
|
Uncertain significance
(Feb 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000780867.29
First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
Comment:
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 233 of the ELOVL4 protein (p.Thr233Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spinocerebellar ataxia (PMID: 30065956, 31105016, 34234304, 34623043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 547008). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ELOVL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ELOVL4 c.698C>T (p.Thr233Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251008 control chromosomes (gnomAD). c.698C>T has been reported in the literature in multiple individuals affected with erythrokeratodermia and spinocerebellar ataxia 34 (examples: Bourque_2018, Ozaki_2019, Benkirane_2021, and Wang_2021). The variant segregated with the disease in multiple families. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30065956, 34234304, 34623043, 31105016). ClinVar contains an entry for this variant (Variation ID: 547008). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30065956, 34623043, 33816655, 33556440, 33655653, 34234304, 31105016, 36696030, 36464075)
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:
DNA sequence analysis of the ELOVL4 gene demonstrated a sequence change, c.698C>T, that results in an amino acid change, p.Thr233Met. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Thr233Met change has been described in one patient with a combination of erythrokeratodermia and spinocerebellar ataxia (SCA34) (PMID: 30065956). The p.Thr233Met change affects a moderately conserved amino acid residue located in a domain of the ELOVL4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr233Met substitution. Subsequent targeted sequence analysis revealed the absence of this sequence change in both parents. The p.Thr233Met sequence change in the ELOVL4 gene appears to be a de novo event in this individual. Based on the de novo and novel nature of this sequence change, we interpret it as likely pathogenic, however functional studies have not been performed to prove this conclusively.
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 233 of the ELOVL4 protein (p.Thr233Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant spinocerebellar ataxia (PMID: 30065956, 31105016, 34234304, 34623043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 547008). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ELOVL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: ELOVL4 c.698C>T (p.Thr233Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251008 control chromosomes (gnomAD). c.698C>T has been reported in the literature in multiple individuals affected with erythrokeratodermia and spinocerebellar ataxia 34 (examples: Bourque_2018, Ozaki_2019, Benkirane_2021, and Wang_2021). The variant segregated with the disease in multiple families. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30065956, 34234304, 34623043, 31105016). ClinVar contains an entry for this variant (Variation ID: 547008). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30065956, 34623043, 33816655, 33556440, 33655653, 34234304, 31105016, 36696030, 36464075)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Progressive symmetric erythrokeratodermia with spinocerebellar ataxia due to ELOVL4 mutation in a Chinese family. | Wang Z | Indian journal of dermatology, venereology and leprology | 2021 | PMID: 34623043 |
| High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. | Benkirane M | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 34234304 |
| Prevalence and clinicoradiological features of spinocerebellar ataxia type 34 in a Japanese ataxia cohort. | Ozaki K | Parkinsonism & related disorders | 2019 | PMID: 31105016 |
| Novel ELOVL4 mutation associated with erythrokeratodermia and spinocerebellar ataxia (SCA 34). | Bourque PR | Neurology. Genetics | 2018 | PMID: 30065956 |
Text-mined citations for rs1554162016 ...
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 Oct 20, 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.