rs150165484

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:3

Conservation

PhyloP100: 1.95

Publications

9 publications found

Variant links:

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]

COL6A3 Gene-Disease associations (from GenCC):

Bethlem myopathy 1A
Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Ullrich congenital muscular dystrophy 1C
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
dystonia 27
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
Ullrich congenital muscular dystrophy 1A
Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056619078).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0009 (137/152274) while in subpopulation NFE AF = 0.00128 (87/68032). AF 95% confidence interval is 0.00106. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.7258C>T	p.Arg2420Trp	missense_variant	Exon 36 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.6640C>T	p.Arg2214Trp	missense_variant	Exon 35 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.5437C>T	p.Arg1813Trp	missense_variant	Exon 33 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 link	c.7258C>T	p.Arg2420Trp	missense_variant	Exon 36 of 44	1	NM_004369.4	ENSP00000295550.4		P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000907

AC:

138

AN:

152156

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000822

AC:

199

AN:

242156

AF XY:

0.000808

show subpopulations

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 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.:

Cov.:

AF XY:

0.000978

AC XY:

704

AN XY:

719878

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32912

American (AMR)

AF:

0.000599

AC:

AN:

43384

Ashkenazi Jewish (ASJ)

AF:

0.0000392

AC:

AN:

25482

East Asian (EAS)

AF:

0.00

AC:

AN:

39550

South Asian (SAS)

AF:

0.0000706

AC:

AN:

84948

European-Finnish (FIN)

AF:

0.00266

AC:

136

AN:

51166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00103

AC:

1137

AN:

1106262

Other (OTH)

AF:

0.000602

AC:

AN:

59776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000900

AC:

137

AN:

152274

Hom.:

Cov.:

AF XY:

0.000954

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41554

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000840

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000831

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

May 06, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Uncertain:1Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tip-toe gait

Pathogenic:1

Mar 25, 2022

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Benign

0.79

DEOGEN2

Uncertain

0.68

.;D;.;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D;D;D;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.057

T;T;T;T;T

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.7

.;M;.;.;.

PhyloP100

1.9

PrimateAI

Benign

0.41

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

GERP RS

3.3

PromoterAI

-0.066

Neutral

(source)

Varity_R

0.21

gMVP

0.62

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over