rs886043576

Variant names:

• chr2-237348653-C-G
• rs886043576
• NM_004369.4:c.6890G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_004369.4(COL6A3):​c.6890G>C​(p.Gly2297Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 6.36

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Collagen-like 4 (size 51) in uniprot entity CO6A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_004369.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925
• PP5: Variant 2-237348653-C-G is Pathogenic according to our data. Variant chr2-237348653-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287133.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Uncertain_significance=1}. Variant chr2-237348653-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6890G>C	p.Gly2297Ala	missense_variant	Exon 29 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6272G>C	p.Gly2091Ala	missense_variant	Exon 28 of 43		NP_476508.2
COL6A3	NM_057166.5	c.5069G>C	p.Gly1690Ala	missense_variant	Exon 26 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6890G>C	p.Gly2297Ala	missense_variant	Exon 29 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5069G>C	p.Gly1690Ala	missense_variant	Exon 26 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6272G>C	p.Gly2091Ala	missense_variant	Exon 28 of 43	5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1144G>C		non_coding_transcript_exon_variant	Exon 6 of 20	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4

Jan 12, 2018

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL6A3: PM1:Strong, PM2, PS4:Supporting -

Jun 28, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COL6A3-related disorder Pathogenic:1

May 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COL6A3 c.6890G>C variant is predicted to result in the amino acid substitution p.Gly2297Ala. This variant has been reported in the heterozygous state in two individuals with unusual progressive limb girdle muscular dystrophy 2A (Table S1, Nallamilli et al. 2018. PubMed ID: 30564623). Both individuals also harbored a homozygous pathogenic variant in the CAPN3 gene. It has also been reported in a male individual from a preconception carrier screening study (Table S1, Capalbo et al. 2019. PubMed ID: 31589614). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant occurs in the conserved Gly-X-Y triple helical domain where substitution of the glycine is usually pathogenic (Butterfield et al. 2013. PubMed ID: 24038877). This variant is interpreted as likely pathogenic. -

Bethlem myopathy 1A Uncertain:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2297 of the COL6A3 protein (p.Gly2297Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and clinical features of collagenopathies (PMID: 30564623, 35487415). ClinVar contains an entry for this variant (Variation ID: 287133). 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). 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	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	.;D;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;.
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D;D;D;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.87
MutPred		0.59		.;Loss of stability (P = 0.0332);.;.;.;
MVP		0.96
MPC		0.16
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.80
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs886043576; hg19: chr2-238257296;