rs267606748

Variant names:

• chr21-46115917-G-A
• rs267606748
• NM_001849.4:c.847G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46115917-G-A
• chr21-46115917-G-C

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001849.4(COL6A2):​c.847G>A​(p.Gly283Arg) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 6.30
• Publications: 6 publications found

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

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

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_001849.4 (COL6A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 871767
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46115918-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-46115917-G-A is Pathogenic according to our data. Variant chr21-46115917-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.847G>A	p.Gly283Arg	missense_variant	Exon 6 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.847G>A	p.Gly283Arg	missense_variant	Exon 6 of 28		NP_478054.2
COL6A2	NM_058175.3	c.847G>A	p.Gly283Arg	missense_variant	Exon 6 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.847G>A	p.Gly283Arg	missense_variant	Exon 6 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.847G>A	p.Gly283Arg	missense_variant	Exon 6 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.847G>A	p.Gly283Arg	missense_variant	Exon 5 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.503G>A		non_coding_transcript_exon_variant	Exon 2 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Mar 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 17167). This missense change has been observed in individual(s) with autosomal dominant Ullrich congenital muscular dystrophy (PMID: 24038877). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 283 of the COL6A2 protein (p.Gly283Arg). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL6A2. 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 COL6A2, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). 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 COL6A2 protein function. -

Ullrich congenital muscular dystrophy 1A Pathogenic:1

Oct 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL6A2 c.847G>A (p.Gly283Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249228 control chromosomes (gnomAD). c.847G>A has been reported in the literature in at least 3 heterozygous individuals affected with (or symptoms suggestive of) Ullrich congenital muscular dystrophy (e.g. Lampe_2005, Nadeau_2009, Brinas_2010, Foley_2013, and in an Internal LCA patient), and in multiple patients the variant was noted to be a de novo occurrence. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15689448, 19564581, 20976770, 24271325). ClinVar contains an entry for this variant (Variation ID: 17167). Based on the evidence outlined above, the variant was classified as pathogenic. -

Ullrich congenital muscular dystrophy 1B Pathogenic:1

Jul 07, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Uncertain:1

Jun 06, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;H
PhyloP100		6.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.4	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.96	D;D;D;D
Vest4		0.99
MutPred		0.96		Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);
MVP		0.97
MPC		0.66
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.96
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs267606748; hg19: chr21-47535831;