NM_004369.4:c.2302C>G

Variant names:

• chr2-237378831-G-C
• rs200722892
• NM_004369.4:c.2302C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004369.4(COL6A3):​c.2302C>G​(p.Arg768Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R768C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.24
• Publications: 3 publications found

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]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AR, SD, AD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-237378831-G-C is Pathogenic according to our data. Variant chr2-237378831-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191156.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.2302C>G	p.Arg768Gly	missense	Exon 6 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.1684C>G	p.Arg562Gly	missense	Exon 5 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057165.5		c.1684C>G	p.Arg562Gly	missense	Exon 5 of 8	NP_476506.3	P12111-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.2302C>G	p.Arg768Gly	missense	Exon 6 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000392004.7	TSL:1	c.1684C>G	p.Arg562Gly	missense	Exon 5 of 8	ENSP00000375861.3	P12111-5
	COL6A3	ENST00000472056.5	TSL:1	c.677-1487C>G		intron	N/A	ENSP00000418285.1	P12111-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Bethlem myopathy 1A (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.39
Sift	Benign	0.097	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.48		Loss of solvent accessibility (P = 0.0044)
MVP		0.90
MPC		0.73
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.50
gMVP		0.58
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200722892; hg19: chr2-238287474;