ClinVar Genomic variation as it relates to human health
NM_001848.3(COL6A1):c.1022G>T (p.Gly341Val)
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_001848.3(COL6A1):c.1022G>T (p.Gly341Val)
Variation ID: 282533 Accession: VCV000282533.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 45990792 (GRCh38) [ NCBI UCSC ] 21: 47410706 (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 6, 2016 Feb 20, 2024 Jan 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001848.3:c.1022G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001839.2:p.Gly341Val missense NC_000021.9:g.45990792G>T NC_000021.8:g.47410706G>T NG_008674.1:g.14044G>T LRG_475:g.14044G>T LRG_475t1:c.1022G>T LRG_475p1:p.Gly341Val P12109:p.Gly341Val - Protein change
- G341V
- Other names
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- Canonical SPDI
- NC_000021.9:45990791:G: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.
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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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COL6A1 | - | - |
GRCh38 GRCh37 |
1780 | 1892 |
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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Pathogenic (1) |
criteria provided, single submitter
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Jan 6, 2024 | RCV000267474.11 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 6, 2018 | RCV000521707.6 | |
COL6A1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Apr 25, 2023 | RCV004535283.1 |
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
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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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Pathogenic
(Apr 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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COL6A1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004120651.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The COL6A1 c.1022G>T variant is predicted to result in the amino acid substitution p.Gly341Val. This variant was reported in the heterozygous state in an an … (more)
The COL6A1 c.1022G>T variant is predicted to result in the amino acid substitution p.Gly341Val. This variant was reported in the heterozygous state in an an individual with Bethlem myopathy and found to segregate in two other affected family members, indicating autosomal dominant inheritance (Lucioli et al 2005. PubMed ID: 15955946). This variant has also been reported to occur de novo in a patient with limb girdle muscular dystrophy and in other patients with features of COL6A1-related disorders (See Table 3 Ghaoui R et al 2015. PubMed ID: 26436962; Deconinck N et al 2010. PubMed ID: 20576434; Table 1 Kim J et al 2011. PubMed ID: 22075033; Deconinck N et al 2014. PubMed ID: 25535305). A different substitution at this position (p.Gly341Asp) has also been reported in a family with autosomal dominant Bethlem myopathy (Scacheri PC et al 2002. PubMed ID: 11865138). This variant disrupts the triple helix domain of COL6A1 and glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (Long et al. 1993. PubMed ID: 8218237; Bella et al. 1994. PubMed ID: 7695699; Shoulders et al. 2009. PubMed ID: 19344236). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic for autosomal dominant COL6A1-related disorders. (less)
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Pathogenic
(Nov 14, 2017)
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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: SCV000334053.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 7
Sex: mixed
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Pathogenic
(Aug 06, 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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GeneDx
Accession: SCV000617763.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
The G341V pathogenic variant in the COL6A1 gene has been previously reported in multiple unrelated individuals with Bethlem myopathy (Lampe et al., 2005; Lucioli et … (more)
The G341V pathogenic variant in the COL6A1 gene has been previously reported in multiple unrelated individuals with Bethlem myopathy (Lampe et al., 2005; Lucioli et al., 2005; Deconinck et al., 2014; Ghaoui et al., 2015). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and G341V was found to be de novo in two cases (Deconinck et al., 2014; Ghaoui et al., 2015). The G341V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. Additionally, a different missense variant at the same position (G341D) has been previously reported in a family with autosomal dominant Bethlem myopathy (Scacheri et al., 2002). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
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Pathogenic
(Jan 06, 2024)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000656970.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the COL6A1 protein (p.Gly341Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the COL6A1 protein (p.Gly341Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant COL6A1-related conditions (PMID: 15689448, 15955946, 20576434, 22075033, 25535305, 26436962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282533). 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 COL6A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL6A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). This variant disrupts the p.Gly341 amino acid residue in COL6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11865138, 24038877). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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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Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. | Ghaoui R | JAMA neurology | 2015 | PMID: 26436962 |
Bethlem myopathy: long-term follow-up identifies COL6 mutations predicting severe clinical evolution. | Deconinck N | Journal of neurology, neurosurgery, and psychiatry | 2015 | PMID: 25535305 |
Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies. | Butterfield RJ | Human mutation | 2013 | PMID: 24038877 |
Flow cytometry analysis: a quantitative method for collagen VI deficiency screening. | Kim J | Neuromuscular disorders : NMD | 2012 | PMID: 22075033 |
Differentiating Emery-Dreifuss muscular dystrophy and collagen VI-related myopathies using a specific CT scanner pattern. | Deconinck N | Neuromuscular disorders : NMD | 2010 | PMID: 20576434 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
Detection of common and private mutations in the COL6A1 gene of patients with Bethlem myopathy. | Lucioli S | Neurology | 2005 | PMID: 15955946 |
Automated genomic sequence analysis of the three collagen VI genes: applications to Ullrich congenital muscular dystrophy and Bethlem myopathy. | Lampe AK | Journal of medical genetics | 2005 | PMID: 15689448 |
Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype. | Scacheri PC | Neurology | 2002 | PMID: 11865138 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A1 | - | - | - | - |
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Text-mined citations for rs121912935 ...
HelpRecord last updated Oct 13, 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.