Variant summary: ABCD4 c.1588C>T (p.Gln530X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been observed in association with inborn error of vitamin B12 metabolism in the HGMD database. The variant allele was found at a frequency of 4e-06 in 249354 control chromosomes. To our knowledge, no occurrence of c.1588C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005050.4(ABCD4):c.1588C>T (p.Gln530Ter)
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.
(3)
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
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005050.4(ABCD4):c.1588C>T (p.Gln530Ter)
Variation ID: 583152 Accession: VCV000583152.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 74287858 (GRCh38) [ NCBI UCSC ] 14: 74754561 (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 Oct 10, 2018 Feb 14, 2024 May 11, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005050.4:c.1588C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005041.1:p.Gln530Ter nonsense NM_001353591.2:c.1462C>T NP_001340520.1:p.Gln488Ter nonsense NM_001353592.2:c.1462C>T NP_001340521.1:p.Gln488Ter nonsense NM_001353593.2:c.1327C>T NP_001340522.1:p.Gln443Ter nonsense NM_001353594.2:c.1276C>T NP_001340523.1:p.Gln426Ter nonsense NM_001353595.2:c.1174C>T NP_001340524.1:p.Gln392Ter nonsense NM_001353596.2:c.1174C>T NP_001340525.1:p.Gln392Ter nonsense NM_001353597.2:c.1123C>T NP_001340526.1:p.Gln375Ter nonsense NM_001353598.2:c.1111C>T NP_001340527.1:p.Gln371Ter nonsense NM_001353599.2:c.1111C>T NP_001340528.1:p.Gln371Ter nonsense NM_001353600.2:c.1111C>T NP_001340529.1:p.Gln371Ter nonsense NM_001353601.2:c.1111C>T NP_001340530.1:p.Gln371Ter nonsense NM_001353602.2:c.799C>T NP_001340531.1:p.Gln267Ter nonsense NM_001353603.2:c.799C>T NP_001340532.1:p.Gln267Ter nonsense NM_001353604.2:c.799C>T NP_001340533.1:p.Gln267Ter nonsense NM_001353605.2:c.799C>T NP_001340534.1:p.Gln267Ter nonsense NM_001353606.2:c.799C>T NP_001340535.1:p.Gln267Ter nonsense NM_001353607.2:c.799C>T NP_001340536.1:p.Gln267Ter nonsense NM_001353608.2:c.799C>T NP_001340537.1:p.Gln267Ter nonsense NM_001353609.2:c.799C>T NP_001340538.1:p.Gln267Ter nonsense NM_001353610.2:c.855C>T NP_001340539.1:p.Cys285= synonymous NM_020324.3:c.1111C>T NP_064720.1:p.Gln371Ter nonsense NM_020325.3:c.1588C>T NP_064730.1:p.Gln530Ter nonsense NR_003256.3:n.1482C>T non-coding transcript variant NR_148466.2:n.1418C>T non-coding transcript variant NR_148467.2:n.1199C>T non-coding transcript variant NR_148468.2:n.1176C>T non-coding transcript variant NR_148469.2:n.1423C>T non-coding transcript variant NR_148470.2:n.1385C>T non-coding transcript variant NR_148471.2:n.1423C>T non-coding transcript variant NR_148472.2:n.1472C>T non-coding transcript variant NR_148473.2:n.1399C>T non-coding transcript variant NR_148474.2:n.1518C>T non-coding transcript variant NC_000014.9:g.74287858G>A NC_000014.8:g.74754561G>A NG_032875.1:g.20207C>T - Protein change
- Q530*, Q267*, Q375*, Q371*, Q426*, Q443*, Q392*, Q488*
- Other names
- -
- Canonical SPDI
- NC_000014.9:74287857:G:A
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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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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
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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. |
|||
| ABCD4 | - | - |
GRCh38 GRCh37 |
430 | 452 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 18, 2017 | RCV000707417.10 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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May 11, 2022 | RCV002265867.1 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(May 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548358.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: ABCD4 c.1588C>T (p.Gln530X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ABCD4 c.1588C>T (p.Gln530X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been observed in association with inborn error of vitamin B12 metabolism in the HGMD database. The variant allele was found at a frequency of 4e-06 in 249354 control chromosomes. To our knowledge, no occurrence of c.1588C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia with homocystinuria, type cblJ
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047863.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The stop gained c.1588C>T (p.Gln530Ter) variant has been submitted to ClinVar as Pathogenic but no evidences are provided for independent assessment. This p.Gln530Ter variant has … (more)
The stop gained c.1588C>T (p.Gln530Ter) variant has been submitted to ClinVar as Pathogenic but no evidences are provided for independent assessment. This p.Gln530Ter variant has allele frequency of 0.00040% in the gnomAD and novel (not in any individuals) in 1000 genome database. The nucleotide change c.1588C>T in ABCD4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another variant in ABCD4 gene, the molecular diagnosis can not be confirmed. The above variant has also been detected in the proband's father. (less)
Clinical Features:
Sepsis (present) , Abnormal metabolism (present)
|
|
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Pathogenic
(Oct 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Methylmalonic acidemia with homocystinuria, type cblJ
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000836515.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABCD4 are known to be pathogenic (PMID: 22922874). Algorithms developed to predict … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABCD4 are known to be pathogenic (PMID: 22922874). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ABCD4-related disease. This variant is present in population databases (rs767795583, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Gln530*) in the ABCD4 gene. It is expected to result in an absent or disrupted protein product. (less)
|
Comment:
Comment:
The stop gained c.1588C>T (p.Gln530Ter) variant has been submitted to ClinVar as Pathogenic but no evidences are provided for independent assessment. This p.Gln530Ter variant has allele frequency of 0.00040% in the gnomAD and novel (not in any individuals) in 1000 genome database. The nucleotide change c.1588C>T in ABCD4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another variant in ABCD4 gene, the molecular diagnosis can not be confirmed. The above variant has also been detected in the proband's father.
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABCD4 are known to be pathogenic (PMID: 22922874). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ABCD4-related disease. This variant is present in population databases (rs767795583, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Gln530*) in the ABCD4 gene. It is expected to result in an absent or disrupted protein product.
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:
Variant summary: ABCD4 c.1588C>T (p.Gln530X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been observed in association with inborn error of vitamin B12 metabolism in the HGMD database. The variant allele was found at a frequency of 4e-06 in 249354 control chromosomes. To our knowledge, no occurrence of c.1588C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
The stop gained c.1588C>T (p.Gln530Ter) variant has been submitted to ClinVar as Pathogenic but no evidences are provided for independent assessment. This p.Gln530Ter variant has allele frequency of 0.00040% in the gnomAD and novel (not in any individuals) in 1000 genome database. The nucleotide change c.1588C>T in ABCD4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another variant in ABCD4 gene, the molecular diagnosis can not be confirmed. The above variant has also been detected in the proband's father.
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABCD4 are known to be pathogenic (PMID: 22922874). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ABCD4-related disease. This variant is present in population databases (rs767795583, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Gln530*) in the ABCD4 gene. It is expected to result in an absent or disrupted protein product.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutations in ABCD4 cause a new inborn error of vitamin B12 metabolism. | Coelho D | Nature genetics | 2012 | PMID: 22922874 |
Text-mined citations for rs767795583 ...
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.