rs139260335
Positions:
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
ENST00000295550.9 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 4.93
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]
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 | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A3 | NM_004369.4 | c.7447A>G | p.Lys2483Glu | missense_variant | 36/44 | ENST00000295550.9 | NP_004360.2 | |
COL6A3 | NM_057167.4 | c.6829A>G | p.Lys2277Glu | missense_variant | 35/43 | NP_476508.2 | ||
COL6A3 | NM_057166.5 | 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 | c.7447A>G | p.Lys2483Glu | missense_variant | 36/44 | 1 | NM_004369.4 | ENSP00000295550 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152198Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
81
AN:
152198
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000612 AC: 154AN: 251446Hom.: 1 AF XY: 0.000677 AC XY: 92AN XY: 135896
GnomAD3 exomes
AF:
AC:
154
AN:
251446
Hom.:
AF XY:
AC XY:
92
AN XY:
135896
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000737 AC: 1077AN: 1461892Hom.: 1 Cov.: 34 AF XY: 0.000737 AC XY: 536AN XY: 727246
GnomAD4 exome
AF:
AC:
1077
AN:
1461892
Hom.:
Cov.:
34
AF XY:
AC XY:
536
AN XY:
727246
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000532 AC: 81AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74356
GnomAD4 genome
AF:
AC:
81
AN:
152198
Hom.:
Cov.:
32
AF XY:
AC XY:
34
AN XY:
74356
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
3
ALSPAC
AF:
AC:
1
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
6
ExAC
AF:
AC:
67
EpiCase
AF:
EpiControl
AF:
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;N
REVEL
Pathogenic
Sift
Benign
D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;.;.;D
Vest4
MVP
MPC
0.21
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at