rs36092870

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_004369.4(COL6A3):​c.1976G>T​(p.Arg659Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R659H) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

COL6A3
NM_004369.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64
Variant links:
Genes affected
COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-237379157-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL6A3NM_004369.4 linkc.1976G>T p.Arg659Leu missense_variant Exon 6 of 44 ENST00000295550.9 NP_004360.2 P12111-1D9ZGF2Q8N4Z1Q63HQ4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL6A3ENST00000295550.9 linkc.1976G>T p.Arg659Leu missense_variant Exon 6 of 44 1 NM_004369.4 ENSP00000295550.4 P12111-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1976G>T (p.R659L) alteration is located in exon 6 (coding exon 5) of the COL6A3 gene. This alteration results from a G to T substitution at nucleotide position 1976, causing the arginine (R) at amino acid position 659 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
.;D;.;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
D;D;.;D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.89
D;D;D;D;D
MetaSVM
Uncertain
0.50
D
MutationAssessor
Benign
1.6
.;L;.;.;.
PrimateAI
Benign
0.48
T
PROVEAN
Pathogenic
-5.4
D;D;D;D;D
REVEL
Pathogenic
0.69
Sift
Benign
0.035
D;D;D;D;T
Sift4G
Benign
0.15
T;T;T;D;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.69
MutPred
0.76
.;Loss of methylation at R659 (P = 0.2259);.;.;.;
MVP
0.95
MPC
0.72
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.59
gMVP
0.69

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238287800; API