rs139260335

Positions:

chr2-237344571-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The ENST00000295550.9(COL6A3):c.7447A>G(p.Lys2483Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000717 in 1,614,090 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

COL6A3
ENST00000295550.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14U:3

Conservation

PhyloP100: 4.93

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-237344571-T-C is Pathogenic according to our data. Variant chr2-237344571-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196977.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Pathogenic=3, Uncertain_significance=3}. Variant chr2-237344571-T-C is described in Lovd as [Likely_pathogenic]. Variant chr2-237344571-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL6A3	NM_004369.4 linkuse as main transcript	c.7447A>G	p.Lys2483Glu	missense_variant	36/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4 linkuse as main transcript	c.6829A>G	p.Lys2277Glu	missense_variant	35/43		NP_476508.2
COL6A3	NM_057166.5 linkuse as main transcript	c.5626A>G	p.Lys1876Glu	missense_variant	33/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.7447A>G	p.Lys2483Glu	missense_variant	36/44	1	NM_004369.4	ENSP00000295550	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000532

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000612

AC:

154

AN:

251446

Hom.:

AF XY:

0.000677

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000737

AC:

1077

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000737

AC XY:

536

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000875

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000532

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000768

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000552

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 02, 2016	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2022	- -
Uncertain significance, flagged submission	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2024	Reported previously as a variant of uncertain significance in the compound heterozygous state and in the homozygous state in patients with Bethlem myopathy, hyperCKemia, and Type 1 fiber predominance on muscle biopsy. One patient who was homozygous for this variant also harbored a pathogenic variant in a separate gene; however, segregation studies could not be completed (PMID: 30706156, 32403337); Reported previously in patients with with suspected limb girdle muscular dystrophy (PMID: 34720847, 30564623); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 37273706, 36964972, 33441455, 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38155714) -

Bethlem myopathy 1A

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 2483 of the COL6A3 protein (p.Lys2483Glu). This variant is present in population databases (rs139260335, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive COL6A3-related conditions (PMID: 20976770, 26247046, 28688748, 29970176, 32403337, 32448721, 32528171, 33596003, 33749658; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 196977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL6A3 protein function. For these reasons, this variant has been classified as Pathogenic. -

COL6A3-related disorder

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 24, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 04, 2024	The COL6A3 c.7447A>G variant is predicted to result in the amino acid substitution p.Lys2483Glu. This variant has been reported the homozygous and compound heterozygous states in multiple individuals with COL6A3-related myopathies (see for example, Panadés-de Oliveira et al. 2019. PubMed ID: 30706156; Villar-Quiles et al. 2021. PubMed ID: 33749658; Zídková et al. 2023. PubMed ID: 37526466) and has also been shown to co-segregate with disease in multiple families (Hunter et al. 2015. PubMed ID: 26247046; Stavusis et al. 2020. PubMed ID: 32448721; Mihaylova et al. 2021. PubMed ID: 33596003; Villar-Quiles et al. 2021. PubMed ID: 33749658). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic for autosomal recessive COL6A3-related myopathies. -

Dystonia 27

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Aug 19, 2022

This sequence variant is a single nucleotide substitution (A>G) at coding nucleotide 7447 in the COL6A3 gene which results in a lysine to glutamic acid amino acid change at residue 2483 in the COL6A3 protein. This is a previously reported variant (ClinVar) which has been observed in homozygous or compound heterozygous state in several individuals with neuromuscular disorders (PMID: 20976770, 32528171, 32448721, 32403337, 29970176, 28688748, 26247046); in most homozygous cases, the neuromuscular disorders were described as mild with preserved ambulation. This variant is present in 170/282838 alleles (0.06011%), including 1 homozygote, in the gnomAD control population dataset. Structural alysis suggests that this amino acid change will alter the ability of COL6A3 protein to interact with binding targets (PMID: 32448721). Multiple bioinformatic tools predict that this amino acid change will be damaging, and the Lys2483 residue is highly conserved in vertebrates. Functiol studies assessing the effect of this variant on protein structure or activity have not been performed, to our knowledge. Based on the available evidence, we consider this variant to be likely pathogenic. ACMG Criteria: BP1, PM3, PP3, PS4 -

Bethlem myopathy 1C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 15, 2024

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 27, 2024

Variant summary: COL6A3 c.7447A>G (p.Lys2483Glu) results in a conservative amino acid change located in the von Willebrand factor, type A (IPR002035) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251446 control chromosomes in the gnomAD database, including 1 homozygote. This frequency does not allow conclusions about variant significance. c.7447A>G has been reported in the literature in multiple individuals affected with Limb-girdle muscular dystrophy and in several cases other causes were ruled out by whole exome seqeuencing (e.g., Brinas_2010, Hunter_2015, Sframeli_2017, Nallamilli_2018, Fichna_2018, Villar-Quiles_2021, ). Affected individuals with variant of interest display a relatively mild phenotype (e.g., Bethlem myopathy), often with proximal muscle weakness, skin abnormalities, and joint contractures, however affected indivduals do not seem to experience complete loss of ambulation (Villar-Quiles_2021). Individuals who are homozygous for this variant exhibit different clinical features to those who are compound heterozygous, and some do not have typical COL6-related myopathy phenotypes (Villar-Quiles_2021). The relatively high allele frequency, including a observed homozygous individual in the control population, as well as the different phenotypes observed in the homozygous patients, lead some authors to suggest that this variant may act as a modulator of the clinical phenotype. These authors reccommend using an in-depth analysis of clinical features and ancillary tests in order to interpret the genetic analysis regarding this variant (Villar-Quiles_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20976770, 29970176, 26247046, 35239206, 30564623, 28688748, 33749658). ClinVar contains an entry for this variant (Variation ID: 196977). Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

.;T;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D;D;D;.

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.43

T;T;T;T;T

MetaSVM

Uncertain

0.049

MutationAssessor

Benign

1.5

.;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.6

N;N;N;.;N

REVEL

Pathogenic

0.83

Sift

Benign

0.042

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.66

MVP

0.86

MPC

0.21

ClinPred

0.051

GERP RS

4.8

Varity_R

0.23

gMVP

0.57

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

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