ClinVar Genomic variation as it relates to human health
NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)
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
-
NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)
Variation ID: 404289 Accession: VCV000404289.18
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q32.2 2: 189011668 (GRCh38) [ NCBI UCSC ] 2: 189876394 (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 Dec 26, 2017 May 1, 2024 Feb 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000090.4:c.4295G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000081.2:p.Arg1432Leu missense NC_000002.12:g.189011668G>T NC_000002.11:g.189876394G>T NG_007404.1:g.42296G>T LRG_3:g.42296G>T LRG_3t1:c.4295G>T LRG_3p1:p.Arg1432Leu - Protein change
- R1432L
- Other names
- -
- Canonical SPDI
- NC_000002.12:189011667:G:T
-
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.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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. |
|||
COL3A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3008 | 3134 |
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000475974.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2023 | RCV001188122.6 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jun 9, 2022 | RCV001574625.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 9, 2021 | RCV002480343.1 |
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
(Jan 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002629582.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R1432L variant (also known as c.4295G>T), located in coding exon 51 of the COL3A1 gene, results from a G to T substitution at nucleotide … (more)
The p.R1432L variant (also known as c.4295G>T), located in coding exon 51 of the COL3A1 gene, results from a G to T substitution at nucleotide position 4295. The arginine at codon 1432 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in a proband and sibling with features of Ehlers-Danlos syndrome (EDS), but who were not reported to have arterial or organ fragility findings associated with vascular EDS (Stembridge NS et al. Am. J. Med. Genet. A, 2015 Aug;167A:1763-72). 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)
|
|
Uncertain significance
(Aug 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002776850.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Uncertain significance
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000541792.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1432 of the COL3A1 protein (p.Arg1432Leu). … (more)
This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1432 of the COL3A1 protein (p.Arg1432Leu). This variant is present in population databases (rs772428340, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 25846194, 33125268; Invitae). ClinVar contains an entry for this variant (Variation ID: 404289). 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 COL3A1 protein function with a negative predictive value of 95%. 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
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004828275.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with two siblings with Ehlers-Danlos-like symptoms without the vascular impairments typical of vascular Ehlers-Danlos (PMID: 25846194, 31075413) and in one individual affected with spontaneous coronary artery dissection (PMID: 33125268). This variant has been identified in 5/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 11
|
|
Uncertain significance
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001355095.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with two siblings with Ehlers-Danlos-like symptoms without the vascular impairments typical of vascular Ehlers-Danlos (PMID: 25846194, 31075413) and in one individual affected with spontaneous coronary artery dissection (PMID: 33125268). This variant has been identified in 5/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
Uncertain significance
(Jun 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001801479.4
First in ClinVar: Aug 21, 2021 Last updated: Mar 04, 2023 |
Comment:
Identified in two siblings, one with features consistent with classical EDS (cEDS) and one with features of hypermobile EDS (hEDS) (Stembridge et al., 2015); Not … (more)
Identified in two siblings, one with features consistent with classical EDS (cEDS) and one with features of hypermobile EDS (hEDS) (Stembridge et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R1265L); This variant is associated with the following publications: (PMID: 34318601, 25846194, 33125268) (less)
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Ehlers-Danlos syndrome, type 4
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect, ClinGen
Accession: SCV001423384.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Uncertain significance and reported on 02-03-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpretted as Uncertain significance and reported on 02-03-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Myopia (disease) (present) , Atrophic scars (present) , Multiple cafe-au-lait spots (present) , Joint hypermobility (present) , Arterial dissection (present) , Abnormality of esophagus morphology … (more)
Myopia (disease) (present) , Atrophic scars (present) , Multiple cafe-au-lait spots (present) , Joint hypermobility (present) , Arterial dissection (present) , Abnormality of esophagus morphology (present) , Abnormal thrombosis (present) , Bruising susceptibility (present) (less)
Indication for testing: Not Provided
Age: 30-39 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-02-03
Testing laboratory interpretation: 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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing. | Carss KJ | Circulation. Genomic and precision medicine | 2020 | PMID: 33125268 |
Type III collagen (COL3A1): Gene and protein structure, tissue distribution, and associated diseases. | Kuivaniemi H | Gene | 2019 | PMID: 31075413 |
Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene. | Stembridge NS | American journal of medical genetics. Part A | 2015 | PMID: 25846194 |
Text-mined citations for rs772428340 ...
HelpRecord last updated May 08, 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.