2-237348359-G-A

Position:

• chr2-237348359-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000295550.9(COL6A3):​c.6956C>T​(p.Pro2319Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2319Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 ENST00000295550.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue 4-hydroxyproline (size 0) in uniprot entity CO6A3_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6956C>T	p.Pro2319Leu	missense_variant	30/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6338C>T	p.Pro2113Leu	missense_variant	29/43		NP_476508.2
COL6A3	NM_057166.5	c.5135C>T	p.Pro1712Leu	missense_variant	27/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6956C>T	p.Pro2319Leu	missense_variant	30/44	1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.5135C>T	p.Pro1712Leu	missense_variant	27/41	1		ENSP00000418285
COL6A3	ENST00000353578.9	c.6338C>T	p.Pro2113Leu	missense_variant	29/43	5		ENSP00000315873
COL6A3	ENST00000491769.1	n.1210C>T		non_coding_transcript_exon_variant	7/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2017

This sequence change replaces proline with leucine at codon 2319 of the COL6A3 protein (p.Pro2319Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL6A3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;.
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.8	D;D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.52
MutPred		0.39		.;Loss of glycosylation at P2319 (P = 0.0454);.;.;.;
MVP		0.95
MPC		0.16
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs751617505; hg19: chr2-238257002;