rs144223596

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_004369.4(COL6A3):c.4510C>T(p.Arg1504Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,614,116 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1504R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 2 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 3.27

Publications

10 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: Benign. The variant received -9 ACMG points.

BP6

Variant 2-237368953-G-A is Benign according to our data. Variant chr2-237368953-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166943.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000618 (94/152222) while in subpopulation NFE AF = 0.0011 (75/68040). AF 95% confidence interval is 0.000901. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4 link	c.4510C>T	p.Arg1504Trp	missense_variant	Exon 10 of 44	ENST00000295550.9	NP_004360.2	P12111-1D9ZGF2Q8N4Z1Q63HQ4
COL6A3	NM_057167.4 link	c.3892C>T	p.Arg1298Trp	missense_variant	Exon 9 of 43		NP_476508.2	P12111-2Q8N4Z1Q63HQ4
COL6A3	NM_057166.5 link	c.2689C>T	p.Arg897Trp	missense_variant	Exon 7 of 41		NP_476507.3	P12111-4B7ZW00

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A3	ENST00000295550.9 link	c.4510C>T	p.Arg1504Trp	missense_variant	Exon 10 of 44	1	NM_004369.4	ENSP00000295550.4	P12111-1
COL6A3	ENST00000472056.5 link	c.2689C>T	p.Arg897Trp	missense_variant	Exon 7 of 41	1		ENSP00000418285.1	P12111-4
COL6A3	ENST00000353578.9 link	c.3892C>T	p.Arg1298Trp	missense_variant	Exon 9 of 43	5		ENSP00000315873.4	P12111-2
COL6A3	ENST00000684597.1 link	c.116-277C>T		intron_variant	Intron 1 of 2			ENSP00000508021.1	A0A804HKQ0

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000434

AC:

109

AN:

251426

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000903

AC:

1320

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000844

AC XY:

614

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00172

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00106

AC:

1178

AN:

1112012

Other (OTH)

AF:

0.00116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

182

272

363

454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.000618

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41454

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68040

Other (OTH)

AF:

0.000955

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000823

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000329

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Jun 03, 2019

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in the heterozygous state as a variant of uncertain significance in an individual with limb-girdle muscular dystrophy (Nallamilli et al., 2018); Reported along with a second COL6A3 variant in a patient with segmental and cervical dystonia and tremor; however, segregation information was not available (Kumar 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: 29411265, 30564623, 31731261) -

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 25, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL6A3 c.4510C>T (p.Arg1504Trp) results in a non-conservative amino acid change located in the von Willebrand factor, type A domain (IPR002035) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 1614116 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in COL6A3 causing Ullrich Congenital Muscular Dystrophy 1, allowing no conclusion about variant significance. c.4510C>T has been reported in the literature in individuals affected with clinical features of COL6A3-related conditions (e.g. Kumar_2019, Meinke_2020, Nallamilli_2018). These reports do not provide unequivocal conclusions about association of the variant with Ullrich Congenital Muscular Dystrophy 1. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Bloks_2024). The following publications have been ascertained in the context of this evaluation (PMID: 39021299, 31731261, 31862442, 30564623). ClinVar contains an entry for this variant (Variation ID: 166943). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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. -

Bethlem myopathy 1A

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

.;D;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.98

D;D;D;D;.

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.65

D;D;D;D;D

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.6

.;H;.;.;.

PhyloP100

3.3

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.2

D;D;D;.;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.014

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.77

MVP

0.96

MPC

0.66

ClinPred

0.22

GERP RS

5.4

Varity_R

0.54

gMVP

0.75

Mutation Taster

=60/40

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