rs1553553625

Variant names:

• chr2-237360132-C-A
• rs1553553625
• NM_004369.4:c.6238G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237360132-C-A
• chr2-237360132-C-G
• chr2-237360132-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004369.4(COL6A3):​c.6238G>T​(p.Gly2080Cys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2080R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.20
• Publications: 1 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: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain 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-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-237360132-C-A is Pathogenic according to our data. Variant chr2-237360132-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2674601.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6238G>T	p.Gly2080Cys	missense_variant	Exon 17 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5620G>T	p.Gly1874Cys	missense_variant	Exon 16 of 43		NP_476508.2
COL6A3	NM_057166.5	c.4417G>T	p.Gly1473Cys	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.6238G>T	p.Gly2080Cys	missense_variant	Exon 17 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4417G>T	p.Gly1473Cys	missense_variant	Exon 14 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5620G>T	p.Gly1874Cys	missense_variant	Exon 16 of 43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ullrich congenital muscular dystrophy 1A Pathogenic:1

Dec 21, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly2080Cys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. This variant is assumed de novo, but maternity and paternity have not been confirmed. The p.Gly2080Cys variant in COL6A3 has been reported in at least 2 individuals with Ullrich congenital muscular dystrophy ( PMID: 24271325, PMID: 29419890, PMID: 25204870, Neurology Apr 2019, 92 (15 Supplement) P5.4-011), and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position (p.Gly2080Asp, p.Gly2080Arg, and p.Gly2080Ser) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation IDs: 194744, 520883, 502583). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Ullrich congenital muscular dystrophy 1. ACMG/AMP Criteria applied: PM5_strong, PP3, PM2_supporting, PS4_supporting (Richards 2015). -

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	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	.;D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.
PhyloP100		7.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.0	D;D;D;.;D
REVEL	Pathogenic	0.99
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		0.97		.;Loss of catalytic residue at P2076 (P = 0.1146);.;.;.;
MVP		0.95
MPC		0.67
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1553553625; hg19: chr2-238268775;