2-237360131-C-T

Variant names:

• chr2-237360131-C-T
• rs794727188
• NM_004369.4:c.6239G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004369.4(COL6A3):​c.6239G>A​(p.Gly2080Asp) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2080C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.20

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Collagen-like 1 (size 59) in uniprot entity CO6A3_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_004369.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-237360132-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-237360131-C-T is Pathogenic according to our data. Variant chr2-237360131-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 194744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237360131-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6239G>A	p.Gly2080Asp	missense_variant	Exon 17 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5621G>A	p.Gly1874Asp	missense_variant	Exon 16 of 43		NP_476508.2
COL6A3	NM_057166.5	c.4418G>A	p.Gly1473Asp	missense_variant	Exon 14 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6239G>A	p.Gly2080Asp	missense_variant	Exon 17 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4418G>A	p.Gly1473Asp	missense_variant	Exon 14 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5621G>A	p.Gly1874Asp	missense_variant	Exon 16 of 43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Replaces the glycine in the canonical Gly-X-Y repeat of the triple helical domain and is expected to disrupt normal protein folding and function, which is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25525159, 27854213, 15689448, 23175733, 24038877, 24413245, 33441455) -

Bethlem myopathy 1A Pathogenic:1

Mar 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2080 of the COL6A3 protein (p.Gly2080Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 194744). 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 COL6A3 protein function with a positive predictive value of 80%. This variant disrupts the triple helix domain of COL6A3. 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 COL6A3, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.82	.;D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;T;D;D;.
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.2	D;D;D;.;D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.96
MutPred		0.99		.;Loss of MoRF binding (P = 0.1098);.;.;.;
MVP		0.96
MPC		0.74
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.98
gMVP		0.99

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: rs794727188; hg19: chr2-238268774; COSMIC: COSV55084650; COSMIC: COSV55084650;