Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum.
ClinVar Genomic variation as it relates to human health
NM_005050.4(ABCD4):c.611T>C (p.Leu204Ser)
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.
Uncertain significance
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.611T>C (p.Leu204Ser)
Variation ID: 940798 Accession: VCV000940798.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 74295911 (GRCh38) [ NCBI UCSC ] 14: 74762614 (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 16, 2020 Aug 18, 2024 Oct 25, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005050.4:c.611T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005041.1:p.Leu204Ser missense NM_001353591.2:c.542+422T>C intron variant NM_001353592.2:c.542+422T>C intron variant NM_001353593.2:c.350T>C NP_001340522.1:p.Leu117Ser missense NM_001353594.2:c.350T>C NP_001340523.1:p.Leu117Ser missense NM_001353595.2:c.197T>C NP_001340524.1:p.Leu66Ser missense NM_001353596.2:c.197T>C NP_001340525.1:p.Leu66Ser missense NM_001353597.2:c.197T>C NP_001340526.1:p.Leu66Ser missense NM_001353598.2:c.134T>C NP_001340527.1:p.Leu45Ser missense NM_001353599.2:c.134T>C NP_001340528.1:p.Leu45Ser missense NM_001353600.2:c.134T>C NP_001340529.1:p.Leu45Ser missense NM_001353601.2:c.134T>C NP_001340530.1:p.Leu45Ser missense NM_001353602.2:c.-84T>C 5 prime UTR NM_001353603.2:c.-84T>C 5 prime UTR NM_001353604.2:c.-84T>C 5 prime UTR NM_001353605.2:c.-84T>C 5 prime UTR NM_001353606.2:c.-84T>C 5 prime UTR NM_001353607.2:c.-84T>C 5 prime UTR NM_001353608.2:c.-84T>C 5 prime UTR NM_001353609.2:c.-84T>C 5 prime UTR NM_001353610.2:c.-84T>C 5 prime UTR NM_020324.3:c.134T>C NP_064720.1:p.Leu45Ser missense NM_020325.3:c.611T>C NP_064730.1:p.Leu204Ser missense NR_003256.3:n.505T>C non-coding transcript variant NR_148466.2:n.628T>C non-coding transcript variant NR_148467.2:n.365T>C non-coding transcript variant NR_148468.2:n.386T>C non-coding transcript variant NR_148469.2:n.633T>C non-coding transcript variant NR_148470.2:n.505T>C non-coding transcript variant NR_148471.2:n.633T>C non-coding transcript variant NR_148472.2:n.587T>C non-coding transcript variant NR_148473.2:n.514T>C non-coding transcript variant NR_148474.2:n.633T>C non-coding transcript variant NC_000014.9:g.74295911A>G NC_000014.8:g.74762614A>G NG_032875.1:g.12154T>C - Protein change
- L66S, L117S, L45S, L204S
- Other names
- -
- Canonical SPDI
- NC_000014.9:74295910:A:G
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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.
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0.00100 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00005
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00023
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00109
- 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. |
|---|---|---|---|---|
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 25, 2022 | RCV001210455.6 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
- | RCV004695183.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Mar 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia with homocystinuria, type cblJ
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breda Genetics srl
Accession: SCV001976364.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. … (more)
Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum. (less)
|
|
|
Uncertain significance
(Oct 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia with homocystinuria, type cblJ
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001381943.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the ABCD4 protein (p.Leu204Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the ABCD4 protein (p.Leu204Ser). This variant is present in population databases (rs538521064, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ABCD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 940798). 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 expected to disrupt ABCD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: not provided
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Breakthrough Genomics, Breakthrough Genomics
Accession: SCV005191474.1
First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024 |
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the ABCD4 protein (p.Leu204Ser). This variant is present in population databases (rs538521064, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ABCD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 940798). 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 expected to disrupt ABCD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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:
Based on allele frequency, in-silico prediction scores and a certain overlap with the clinical phenotype, we interpreted this variant at least as of uncertain significance. The lack of one or more of the following features has discouraged further investigations: lack of a possible second hit in autosomal recessive conditions, presence of healthy controls in databases for autosomal dominant conditions, presence of unmatching cardinal clinical features in the patient or in the known gene-disease association, and/or variant type outside the known gene mutational spectrum.
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 204 of the ABCD4 protein (p.Leu204Ser). This variant is present in population databases (rs538521064, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ABCD4-related conditions. ClinVar contains an entry for this variant (Variation ID: 940798). 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 expected to disrupt ABCD4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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 rs538521064 ...
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.