rs1556425468

Positions:

• chr21-45989103-G-A
• chr21-45989103-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001848.3(COL6A1):​c.824G>A​(p.Gly275Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. G275R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.56

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-45989103-G-A is Pathogenic according to our data. Variant chr21-45989103-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1328167.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-45989103-G-A is described in Lovd as [Pathogenic]. Variant chr21-45989103-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-45989103-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.824G>A	p.Gly275Glu	missense_variant	9/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.824G>A	p.Gly275Glu	missense_variant	9/35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Collagen 6-related myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 01, 2021

The COL6A1 c.824G>A (p.Gly275Glu) variant is a missense variant that has been reported in a heterozygous state in at least two studies in two individuals with Bethlem myopathy (Hicks et al. 2008; Lee et al. 2017). Alternative missense changes at the same position, p.Gly275Arg and p.Gly275Trp, are reported in at least two individuals with Bethlem myopathy (Lucioli et al. 2005; Choi et al. 2020). The p.Gly275Glu variant is not found in the Genome Aggregation Database, version 2.1.1 and version 3.1.1, in a region of good sequence coverage, so the variant is presumed to be rare. The p.Gly275Glu variant is located in the highly conserved Gly-X-Y motif of the triple helix domain of collagen type VI, and glycine-affecting missense variants in this region are a common pathogenic mechanism in collagen type VI-related disorders (Lamandé et al. 2002; Lampe et al. 2005). Based on the evidence, the p.Gly275Glu variant is classified as pathogenic for collagen type VI-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;T
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	H;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.98		Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);
MVP		0.99
MPC		0.29
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.93
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47409017;