21-45987638-G-T

Variant names:

• chr21-45987638-G-T
• rs886043351
• NM_001848.3:c.788G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001848.3(COL6A1):​c.788G>T​(p.Gly263Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G263D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.49
• Publications: 2 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-45987638-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286252.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 21-45987638-G-T is Pathogenic according to our data. Variant chr21-45987638-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 570612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.788G>T	p.Gly263Val	missense_variant	Exon 8 of 35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.788G>T	p.Gly263Val	missense_variant	Exon 8 of 35	1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000492851.1	n.*5G>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Jun 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with valine at codon 263 of the COL6A1 protein (p.Gly263Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL6A1-related disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 15689448, 24038877) compared to the general population (ExAC). -

Collagen 6-related myopathy Pathogenic:1

Feb 10, 2025

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2_supporting: this variant is absent from gnomAD exomes and genomes (coverage >20X confirmed) and an internal database. PP3_strong: REVEL score is 0.947. PM1 met: ~40% of pathogenic COL6A1 variants occur in the collagen triple helix (TH) repeat domain and these are heavily clustered in a short segment N-terminal to the 17th Gly-X-Y triplet, where they act as dominant mutations (PMID 24038877). This variant involves a glycine substitution in the third Gly-X-Y triplet of the collagen TH repeat domain which lies outside the critical region (Gly-X-Y triplets 10-15) associated with a more severe disruption of collagen 6 assembly and a more severe clinical phenotype (PMID 18825676, 24038877). PM5 met: COL6A1 p.Gly263Asp is classified as pathogenic (ClinVar accession SCV002311486.2 documenting multiple observations in individuals with clinical features of autosomal dominant COL6A1-related conditions and segregation with disease in related individuals- Invitae). PS4_supporting: this variant has been reported in 1 unrelated proband with consistent phenotype for disorder (ClinVar accession SCV000819297.3, adult male with undifferentiated muscular dystrophy, complicated paraplegia and respiratory failure- personal communication). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;.
PhyloP100		4.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.95		Loss of catalytic residue at P259 (P = 0.113);Loss of catalytic residue at P259 (P = 0.113);
MVP		0.99
MPC		0.28
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.97
gMVP		0.99
Mutation Taster		=49/51	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886043351; hg19: chr21-47407552;