chr2-237344760-G-A

Position:

• chr2-237344760-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004369.4(COL6A3):​c.7258C>T​(p.Arg2420Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000924 in 1,601,450 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. R2420Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 1.95

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056619078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.7258C>T	p.Arg2420Trp	missense_variant	36/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6640C>T	p.Arg2214Trp	missense_variant	35/43
COL6A3	NM_057166.5	c.5437C>T	p.Arg1813Trp	missense_variant	33/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7258C>T	p.Arg2420Trp	missense_variant	36/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.5437C>T	p.Arg1813Trp	missense_variant	33/41	1
COL6A3	ENST00000353578.9	c.6640C>T	p.Arg2214Trp	missense_variant	35/43	5
COL6A3	ENST00000491769.1	n.1512C>T		non_coding_transcript_exon_variant	13/20	5

Frequencies

GnomAD3 genomes AF: 0.000907 AC: 138 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000822 AC: 199 AN: 242156 Hom.: 0 AF XY: 0.000808 AC XY: 106 AN XY: 131202

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.000480

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00327

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000927 AC: 1343 AN: 1449176 Hom.: 0 Cov.: 34 AF XY: 0.000978 AC XY: 704 AN XY: 719878

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000599

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000706

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00103

Gnomad4 OTH exome AF: 0.000602

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74450

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000857 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.00104

EpiControl AF: 0.000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in published literature in the heterozygous state, identified via direct sequencing of COL6A3 in a 63 year old individual with focal dystonia (Zech et al., 2015); This variant is associated with the following publications: (PMID: 30564623, 29970176, 30467950, 26004199) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2017	- -

Bethlem myopathy 1A Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Tip-toe gait Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Mar 25, 2022

Our patients have a gait disorder in the form of a toe walking gait, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene). Myopathy patients (children to the age of 14) typically suffer from hypotrophic muscles and a stress tremor but no pes cavus (Pomarino et al. 2024). Myopathy refers to diseases that affect skeletal Muscles. These diseases attack muscle fibers, making muscles weak. Inherited myopathies are often caused by inheriting an abnormal gene mutation from a parent that causes the disease. Symptoms of congenital myopathies usually start at birth or in early childhood, but may not appear until the teen years or even later in adulthood. Congenital myopathies are somewhat unique compared with other inherited myopathies, as weakness typically affects all muscles and is often not progressive. Symptoms are: Muscle weakness, most commonly of upper arms and shoulders and thighs, muscle cramps, stiffness and spasms, fatigue with exertion and lack of energy. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed. -

Collagen 6-related myopathy Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.79
DEOGEN2	Uncertain	0.68	.;D;.;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.057	T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.7	.;M;.;.;.
MutationTaster	Benign	0.82	D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-5.7	D;D;D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0050	D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;P;.;.;D
Vest4		0.60
MVP		0.94
MPC		0.15
ClinPred		0.11	T
GERP RS		3.3
Varity_R		0.21
gMVP		0.62

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: rs150165484; hg19: chr2-238253403; COSMIC: COSV55083942; COSMIC: COSV55083942;