ClinVar Genomic variation as it relates to human health
NM_000302.4(PLOD1):c.124C>T (p.Arg42Cys)
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_000302.4(PLOD1):c.124C>T (p.Arg42Cys)
Variation ID: 459806 Accession: VCV000459806.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.22 1: 11948023 (GRCh38) [ NCBI UCSC ] 1: 12008080 (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 14, 2018 May 12, 2024 Mar 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000302.4:c.124C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000293.2:p.Arg42Cys missense NM_001316320.2:c.265C>T NP_001303249.1:p.Arg89Cys missense NC_000001.11:g.11948023C>T NC_000001.10:g.12008080C>T NG_008159.1:g.18335C>T - Protein change
- R42C, R89C
- Other names
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- Canonical SPDI
- NC_000001.11:11948022:C:T
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
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
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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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PLOD1 | - | - |
GRCh38 GRCh37 |
1157 | 1220 |
Conditions - Germline
Condition
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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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2020 | RCV000786194.25 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 25, 2022 | RCV000544097.15 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 6, 2024 | RCV002314963.9 |
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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Uncertain significance
(Oct 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, kyphoscoliotic type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631691.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 42 of the PLOD1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 42 of the PLOD1 protein (p.Arg42Cys). This variant is present in population databases (rs202003686, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLOD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 459806). 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 PLOD1 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)
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Uncertain significance
(Mar 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000739520.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.R42C variant (also known as c.124C>T), located in coding exon 2 of the PLOD1 gene, results from a C to T substitution at nucleotide … (more)
The p.R42C variant (also known as c.124C>T), located in coding exon 2 of the PLOD1 gene, results from a C to T substitution at nucleotide position 124. The arginine at codon 42 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Nov 27, 2020)
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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: SCV001770468.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Jul 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001502494.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Jul 13, 2017)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924902.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
PLOD1, Exon 2, c.124C>T (p.Arg42Cys) - Heterozygous (NM_000302.3) Chromosome location 1:12008080 C / T Testing was conducted at Invitae laboratory. The PLOD1 gene is associated … (more)
PLOD1, Exon 2, c.124C>T (p.Arg42Cys) - Heterozygous (NM_000302.3) Chromosome location 1:12008080 C / T Testing was conducted at Invitae laboratory. The PLOD1 gene is associated with autosomal recessive Ehlers-Danlos syndrome, kyphoscoliotic form (MedGen UID: 75672). Our patient has not been diagnosed with this condition. We classify this as a Variant of Uncertain Significance (VUS). Because Ehlers-Danlos syndrome, kyphoscoliotic form, is autosomal recessive, any single variant is not expected to cause disease. This variant has not been reported in the literature in association with disease. It has not yet been reported to ClinVar. There are no missense variants listed in ClinVar as Likely Pathogenic or Pathogenic within 10 amino acids of this codon. Of note, the variants in this gene that are classified in ClinVar as Pathogenic are predominantly truncating: nonsense, frameshift, and splice site variants—and are not missense variants like this one. The Arginine at codon 42 is conserved across mammals but is poorly conserved across other vertebrate species. Cysteine is not the default amino acid in any species. This is a nonconservative amino acid change, from a positively-charged Arginine to a polar Cysteine capable of forming disulfide bridges. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is present in 25 out of 140,000 individuals in gnomAD, for an overall MAF of 0. 009%. The highest MAF is among individuals with non-Finnish European ancestry: 0.01657% (21/126,728 alleles). (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
HelpThere 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 rs202003686 ...
HelpRecord last updated May 12, 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.