ClinVar Genomic variation as it relates to human health
NM_000393.5(COL5A2):c.1412G>C (p.Gly471Ala)
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_000393.5(COL5A2):c.1412G>C (p.Gly471Ala)
Variation ID: 429323 Accession: VCV000429323.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q32.2 2: 189066772 (GRCh38) [ NCBI UCSC ] 2: 189931498 (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 Dec 19, 2017 Feb 20, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000393.5:c.1412G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000384.2:p.Gly471Ala missense NC_000002.12:g.189066772C>G NC_000002.11:g.189931498C>G NG_011799.3:g.163530G>C LRG_738:g.163530G>C LRG_738t1:c.1412G>C LRG_738p1:p.Gly471Ala - Protein change
- G471A
- Other names
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- Canonical SPDI
- NC_000002.12:189066771:C:G
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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.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
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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COL5A2 | - | - |
GRCh38 GRCh37 |
1763 | 1798 |
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 (1) |
criteria provided, single submitter
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May 16, 2019 | RCV000494214.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV002231162.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 24, 2022 | RCV002272260.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 10, 2022 | RCV002395194.8 |
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
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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
(May 16, 2019)
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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: SCV000581863.4
First in ClinVar: Jul 02, 2017 Last updated: Apr 17, 2019 |
Comment:
Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 429323; … (more)
Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 429323; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect (less)
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Uncertain significance
(Jun 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, classic type, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557670.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a likely mechanism of … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with classic type Ehlers-Danlos syndrome 2 (MIM#130010) (GeneReviews; PMIDs: 23587214, 20847697). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial and interfamilial phenotypic variability have been reported (GeneReviews, PMID: 20847697). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant affects the glycine residue of the Gly-X-Y repeat within the triple helical domain (PMID: 26608033). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by two clinical diagnostic laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Jun 10, 2022)
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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: SCV002696527.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.G471A variant (also known as c.1412G>C), located in coding exon 22 of the COL5A2 gene, results from a G to C substitution at nucleotide … (more)
The p.G471A variant (also known as c.1412G>C), located in coding exon 22 of the COL5A2 gene, results from a G to C substitution at nucleotide position 1412. The glycine at codon 471 is replaced by alanine, an amino acid with similar properties. Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif of the triple helical domain in the COL5A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci.U.S.A. 2008;105:18273-7; Ambry internal data). Glycine substitutions in the triple helical domain of COL5A2 have been reported in association with classic Ehlers-Danlos syndrome (cEDS), but the number of affected individuals is limited and several other COL5A2 glycine substitutions in the triple helical domain (e.g., p.G951E and p.G831A) are too common for disease in population databases (Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93; Ritelli M et al. Orphanet J Rare Dis. 2013 Apr;8:58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Mar 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, classic type, 2
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003833738.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Uncertain significance
(Nov 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, classic type, 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631566.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 471 of the COL5A2 protein (p.Gly471Ala). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 471 of the COL5A2 protein (p.Gly471Ala). This variant is present in population databases (rs779614415, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 429323). 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 COL5A2 protein function with a negative predictive value of 80%. 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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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 |
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Structural in silico dissection of the collagen V interactome to identify genotype-phenotype correlations in classic Ehlers-Danlos Syndrome (EDS). | Paladin L | FEBS letters | 2015 | PMID: 26608033 |
Clinical and molecular characterization of 40 patients with classic Ehlers-Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations. | Ritelli M | Orphanet journal of rare diseases | 2013 | PMID: 23587214 |
Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. | Malfait F | Genetics in medicine : official journal of the American College of Medical Genetics | 2010 | PMID: 20847697 |
Text-mined citations for rs779614415 ...
HelpRecord last updated Apr 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.