rs369810455

Positions:

• chr2-237374901-G-A
• chr2-237374901-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4 BP6

The NM_004369.4(COL6A3):​c.3190C>T​(p.Arg1064Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1064Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.99

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-237374900-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.33680892).
• BP6: Variant 2-237374901-G-A is Benign according to our data. Variant chr2-237374901-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 335132.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.3190C>T	p.Arg1064Trp	missense_variant	8/44	ENST00000295550.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.3190C>T	p.Arg1064Trp	missense_variant	8/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 35 AN: 249566 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135094

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000893

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 727210

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7 AN XY: 74172

Gnomad4 AFR AF: 0.000363

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	Reported in a patient with cerebral palsy (Pingel et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30467950) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2017	- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D;D;D;D;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;D;.;.
Vest4		0.60
MVP		0.91
MPC		0.66
ClinPred		0.21	T
GERP RS		4.4
Varity_R		0.60
gMVP		0.77

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: rs369810455; hg19: chr2-238283544; COSMIC: COSV55079444; COSMIC: COSV55079444;