rs121912940

Positions:

• chr21-46115881-G-A

Variant summary

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

The ENST00000300527.9(COL6A2):​c.811G>A​(p.Gly271Ser) 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. G271D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 ENST00000300527.9 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.30

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 4 uncertain in ENST00000300527.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46115882-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 198136.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 21-46115881-G-A is Pathogenic according to our data. Variant chr21-46115881-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46115881-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.811G>A	p.Gly271Ser	missense_variant	6/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.811G>A	p.Gly271Ser	missense_variant	6/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.811G>A	p.Gly271Ser	missense_variant	6/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.811G>A	p.Gly271Ser	missense_variant	6/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.811G>A	p.Gly271Ser	missense_variant	6/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.811G>A	p.Gly271Ser	missense_variant	5/27	5		ENSP00000387115
COL6A2	ENST00000485591.1	n.467G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 271 of the COL6A2 protein (p.Gly271Ser). 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. ClinVar contains an entry for this variant (Variation ID: 17155). This variant is also known as G250S. This missense change has been observed in individuals with autosomal dominant Bethlem myopathy (PMID: 8782832). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

May 24, 2019

- -

Bethlem myopathy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.99
MutPred		0.95		Gain of phosphorylation at G271 (P = 0.0203);Gain of phosphorylation at G271 (P = 0.0203);Gain of phosphorylation at G271 (P = 0.0203);Gain of phosphorylation at G271 (P = 0.0203);
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.94

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: rs121912940; hg19: chr21-47535795;