rs201888442

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004369.4(COL6A3):c.8978G>A(p.Arg2993His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R2993C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 0.423

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.027026117).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.8978G>A	p.Arg2993His	missense_variant	41/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.8360G>A	p.Arg2787His	missense_variant	40/43
COL6A3	NM_057166.5 linkuse as main transcript	c.7157G>A	p.Arg2386His	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.8978G>A	p.Arg2993His	missense_variant	41/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000287

AC:

AN:

250812

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000235

AC:

343

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000250

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000229

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	The R2993H variant in the COL6A3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R2993H variant is observed in 15/25792 (0.058%) alleles from individuals of Finnish background, and 75/276520 total alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The R2993H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret R2993H as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 03, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 14, 2023

Variant summary: COL6A3 c.8978G>A (p.Arg2993His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251564 control chromosomes. It was also identified in at least one control individual from a case-control study (Zech_2015). To our knowledge, no occurrence of c.8978G>A in individuals affected with Ullrich Congenital Muscular Dystrophy 1 and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26004199). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; four submitters classified the variant as uncertain significance, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

COL6A3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

The COL6A3 c.8978G>A variant is predicted to result in the amino acid substitution p.Arg2993His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.072% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-238243520-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Bethlem myopathy 1A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.68

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.88

D;D;D;D;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.027

T;T;T;T;T

MetaSVM

Benign

-0.32

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.97

N;N;N;.;N

REVEL

Uncertain

0.36

Sift

Benign

0.032

D;D;D;.;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

0.45

B;P;.;.;B

Vest4

0.18

MVP

0.78

MPC

0.18

ClinPred

0.023

GERP RS

2.5

Varity_R

0.040

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over