rs139260335

chr2-237344571-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004369.4(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 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:3
• 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]

ACMG classification

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=6, Pathogenic=4, Uncertain_significance=2}. 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	UniProt
COL6A3	NM_004369.4	c.7447A>G	p.Lys2483Glu	missense_variant	36/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6829A>G	p.Lys2277Glu	missense_variant	35/43
COL6A3	NM_057166.5	c.5626A>G	p.Lys1876Glu	missense_variant	33/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7447A>G	p.Lys2483Glu	missense_variant	36/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152198 Hom.: 0 Cov.: 32

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.: 1 AF XY: 0.000677 AC XY: 92 AN XY: 135896

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.: 1 Cov.: 34 AF XY: 0.000737 AC XY: 536 AN XY: 727246

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: 81 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74356

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.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.000709

EpiControl AF: 0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:11 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Feb 02, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2023	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 supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 37526466, 30706156, 34720847) -

Bethlem myopathy 1A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
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	- -

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 29, 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 18, 2023

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 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. Eight ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments (likely pathogenic, n=4; pathogenic, n=2, VUS, n=2) and some submitters cite overlapping evidence utalized in the context of this evaluation. 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	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;.
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.049	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
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	T
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

Other links and lift over

dbSNP: rs139260335; hg19: chr2-238253214; COSMIC: COSV99040629; COSMIC: COSV99040629;