ClinVar Genomic variation as it relates to human health
NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys)
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.
Pathogenic(2); Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004369.4(COL6A3):c.6199G>A (p.Glu2067Lys)
Variation ID: 284554 Accession: VCV000284554.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 237361132 (GRCh38) [ NCBI UCSC ] 2: 238269775 (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 Jul 2, 2017 May 12, 2024 Sep 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004369.4:c.6199G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004360.2:p.Glu2067Lys missense NM_057166.5:c.4378G>A NP_476507.3:p.Glu1460Lys missense NM_057167.4:c.5581G>A NP_476508.2:p.Glu1861Lys missense NC_000002.12:g.237361132C>T NC_000002.11:g.238269775C>T NG_008676.1:g.58076G>A LRG_473:g.58076G>A LRG_473t1:c.6199G>A LRG_473p1:p.Glu2067Lys - Protein change
- E2067K, E1460K, E1861K
- Other names
- NM_004369.3(COL6A3):c.6199G>A
- p.Glu2067Lys
- Canonical SPDI
- NC_000002.12:237361131: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
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
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
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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COL6A3 | - | - |
GRCh38 GRCh37 |
3207 | 3405 |
Conditions - Germline
Condition
Help
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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Mar 22, 2022 | RCV000494333.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 4, 2023 | RCV000817700.10 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jul 11, 2022 | RCV002227468.4 |
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
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
(Mar 16, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000337216.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Likely pathogenic
(Jul 31, 2015)
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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: SCV000581855.4
First in ClinVar: Jul 02, 2017 Last updated: Mar 31, 2019 |
Comment:
The E2067K variant has been reported previously in an individual with Bethlem myopathy who was heterozygous for this change and did not have another identifiable … (more)
The E2067K variant has been reported previously in an individual with Bethlem myopathy who was heterozygous for this change and did not have another identifiable pathogenic variant; however, additional clinical information was not provided and functional characterization of the variant was not completed (Foley et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E2067K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and multiple missense variants in nearby residues (G2065D, G2074C/D, P2075L) have been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, the variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. (less)
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Pathogenic
(Aug 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Bethlem myopathy 1A
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976753.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PS2, PM1, PM2, PP3, PP5
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Pathogenic
(Sep 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Bethlem myopathy 1A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000958278.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2067 of the COL6A3 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2067 of the COL6A3 protein (p.Glu2067Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant Bethlem myopathy or limb-girdle muscular dystrophy (PMID: 24271325, 26436962, 30564623; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 284554). 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 COL6A3 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Jul 01, 2018)
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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: SCV000892637.23
First in ClinVar: Mar 31, 2019 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(May 04, 2022)
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criteria provided, single submitter
Method: curation
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Ullrich congenital muscular dystrophy 1A
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV002507000.1
First in ClinVar: May 16, 2022 Last updated: May 16, 2022 |
Comment:
The heterozygous p.Glu2067Lys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. The variant has been reported … (more)
The heterozygous p.Glu2067Lys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. The variant has been reported in 4 individuals of Australian and unknown ethnicity with Ullrich congenital muscular dystrophy 1 (PMID: 30564623, 26436962, 24271325), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 284554) as likely pathogenic by GeneDx, and as having uncertain significance by Invitae, CeGaT Praxis fuer Humangenetik Tuebingen, and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PS4_supporting, PP3 (Richards 2015). (less)
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Likely pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003829731.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jul 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ullrich congenital muscular dystrophy 1A
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV004847227.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Method: Exome sequencing
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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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Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. | Nallamilli BRR | Annals of clinical and translational neurology | 2018 | PMID: 30564623 |
Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. | Ghaoui R | JAMA neurology | 2015 | PMID: 26436962 |
Natural history of pulmonary function in collagen VI-related myopathies. | Foley AR | Brain : a journal of neurology | 2013 | PMID: 24271325 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3 | - | - | - | - |
Text-mined citations for rs760446904 ...
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.