ClinVar Genomic variation as it relates to human health
NM_000093.5(COL5A1):c.1831C>T (p.Arg611Trp)
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.
Uncertain significance(3); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000093.5(COL5A1):c.1831C>T (p.Arg611Trp)
Variation ID: 212943 Accession: VCV000212943.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 134756768 (GRCh38) [ NCBI UCSC ] 9: 137648614 (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 Jan 7, 2017 Apr 15, 2024 Sep 18, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000093.5:c.1831C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000084.3:p.Arg611Trp missense NM_001278074.1:c.1831C>T NP_001265003.1:p.Arg611Trp missense NC_000009.12:g.134756768C>T NC_000009.11:g.137648614C>T NG_008030.1:g.119963C>T LRG_737:g.119963C>T LRG_737t1:c.1831C>T LRG_737p1:p.Arg611Trp LRG_737t2:c.1831C>T LRG_737p2:p.Arg611Trp - Protein change
- R611W
- Other names
- p.R611W:CGG>TGG
- Canonical SPDI
- NC_000009.12:134756767: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
Exome Aggregation Consortium (ExAC) 0.00010
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
1000 Genomes Project 30x 0.00031
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 | ||
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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. |
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COL5A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2630 | 3414 |
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. |
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not provided (1) |
no classification provided
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- | RCV001249369.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Feb 9, 2023 | RCV001705094.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 18, 2023 | RCV002228843.15 |
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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Uncertain significance
(Jan 01, 2023)
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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: SCV003917731.7
First in ClinVar: Apr 23, 2023 Last updated: Apr 15, 2024 |
Comment:
COL5A1: PP3
Number of individuals with the variant: 1
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Uncertain significance
(Sep 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, classic type, 1
(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: SCV002767922.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with classic type Ehlers-Danlos syndrome 1 (MIM#130000). Dominant negative is a suggested mechanism of disease (PMID: 32720758). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2 & v3: 28 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 20 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated triple helical domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg611Gln) has been reported as a VUS, including in an individual with suspected aortopathy (ClinVar, VCGS). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS, including in three affected individuals (ClinVar, VCGS, PMID: 32938213). It has also been reported in an individual with classic Ehlers-Danlos syndrome (PMID: 33161638). However, it has also been reported as likely benign once in ClinVar without further information provided. (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
(Feb 09, 2023)
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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: SCV000249799.8
First in ClinVar: Oct 11, 2015 Last updated: Feb 18, 2023 |
Comment:
Has not been previously reported as pathogenic or benign in association with cEDS to our knowledge; In silico analysis supports that this missense variant has … (more)
Has not been previously reported as pathogenic or benign in association with cEDS to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 29924831, 32938213, 36043395, 33161638) (less)
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Likely benign
(Sep 18, 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: SCV000755928.7
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Ehlers-Danlos syndrome classic type 2
Ehlers-Danlos syndrome, type 1
Affected status: unknown
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV001423358.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Uncertain significance and reported on 07-18-2019 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 07-18-2019 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:
Prenatal maternal abnormality (present) , Premature birth (present) , Hyperthyroidism (present) , Anxiety (present) , Depressivity (present) , Short attention span (present) , Fragile skin … (more)
Prenatal maternal abnormality (present) , Premature birth (present) , Hyperthyroidism (present) , Anxiety (present) , Depressivity (present) , Short attention span (present) , Fragile skin (present) , Cutaneous photosensitivity (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present) , Abnormality of muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the stomach (present) , Gastrointestinal dysmotility (present) , Abnormality of the intestine (present) , Abnormality of the bladder (present) , Abnormality of urine homeostasis (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-07-18
Testing laboratory interpretation: Uncertain significance
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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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Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen-related genes. | Fager Ferrari M | Haemophilia : the official journal of the World Federation of Hemophilia | 2021 | PMID: 33161638 |
A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia. | Richer J | Arteriosclerosis, thrombosis, and vascular biology | 2020 | PMID: 32938213 |
Identification of the novel COL5A1 c.3369_3431dup, p.(Glu1124_Gly1144dup) variant in a patient with incomplete classical Ehlers-Danlos syndrome: The importance of phenotype-guided genetic testing. | Ritelli M | Molecular genetics & genomic medicine | 2020 | PMID: 32720758 |
Text-mined citations for rs147329970 ...
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.