VCV000196977.84 - ClinVar

NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(17)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(9); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

Variation ID: 196977 Accession: VCV000196977.84

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 237344571 (GRCh38) [ NCBI UCSC ] 2: 238253214 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Jan 19, 2025	Jan 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_004369.4:c.7447A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004360.2:p.Lys2483Glu	missense
NM_057166.5:c.5626A>G	NP_476507.3:p.Lys1876Glu	missense
NM_057167.4:c.6829A>G	NP_476508.2:p.Lys2277Glu	missense
NC_000002.12:g.237344571T>C
NC_000002.11:g.238253214T>C
NG_008676.1:g.74637A>G
LRG_473:g.74637A>G
LRG_473t1:c.7447A>G	LRG_473p1:p.Lys2483Glu

... more HGVS ... less HGVS

Protein change

K2483E, K1876E, K2277E

Other names

COL6A3, LYS2483GLU (rs139260335)

Canonical SPDI

NC_000002.12:237344570:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00054

Exome Aggregation Consortium (ExAC) 0.00055

The Genome Aggregation Database (gnomAD) 0.00057

The Genome Aggregation Database (gnomAD), exomes 0.00061

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

Links

ClinGen: CA244831 OMIM: 120250.0012 dbSNP: rs139260335 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL6A3		-	-	GRCh38 GRCh37	3281	3484

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jan 8, 2025	RCV000177877.45
Bethlem myopathy 1A	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 13, 2024	RCV000352490.27
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2024	RCV003114326.12
COL6A3-related disorder	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 24, 2023	RCV003387788.5
Bethlem myopathy 1C	Pathogenic (1)	no assertion criteria provided	Jul 15, 2024	RCV004589832.1
Dystonia 27	Likely pathogenic (1)	criteria provided, single submitter	Aug 19, 2022	RCV004783757.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 05, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331642.4 First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3 Number of individuals with the variant: 11 Zygosity: Single Heterozygote Sex: mixed
Likely pathogenic (Jan 14, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Bethlem myopathy 1A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149742.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Zygosity: Homozygote Sex: male Tissue: blood
Likely pathogenic (Feb 02, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449836.1 First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020	Number of individuals with the variant: 2
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Bethlem myopathy 1A Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518761.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Likely pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	COL6A3-related disorders Affected status: yes Allele origin: germline	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) Accession: SCV003920752.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Likely pathogenic (Aug 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003829720.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bethlem myopathy 1A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000657402.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (10) PubMed: 28492532‚ 20976770‚ 26247046‚ 28688748‚ 29970176‚ 32403337‚ 32448721‚ 32528171‚ 33596003‚ 33749658 Comment: 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 … (more) 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. (less)
Likely pathogenic (May 24, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	COL6A3-related disorders Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV005045493.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024
Likely pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197627.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Uncertain significance (Jun 27, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003800970.3 First in ClinVar: Feb 13, 2023 Last updated: Sep 16, 2024	Publications: PubMed (7) PubMed: 30564623‚ 29970176‚ 28688748‚ 20976770‚ 26247046‚ 33749658‚ 35239206 Comment: 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 … (more) 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. (less)
Likely Pathogenic (Aug 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dystonia 27 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV005397330.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (7) PubMed: 20976770‚ 32528171‚ 29970176‚ 32403337‚ 28688748‚ 26247046‚ 32448721 Comment: 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 … (more) 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 (less)
Likely pathogenic (Sep 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001962365.21 First in ClinVar: Oct 08, 2021 Last updated: Dec 22, 2024	Number of individuals with the variant: 1
Likely pathogenic (Jan 08, 2025)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000564904.12 First in ClinVar: Jun 29, 2015 Last updated: Jan 19, 2025	Comment: Reported previously in the compound heterozygous state and in the homozygous state in patients with Bethlem myopathy, hyperCKemia, and Type 1 fiber predominance on muscle … (more) Reported previously 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, 38155714); 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: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38127101, 38155714, 36964972, 33441455, 37273706) (less)
Pathogenic (Jul 15, 2024)	no assertion criteria provided Method: literature only	BETHLEM MYOPATHY 1C, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV005077970.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 30706156‚ 33749658 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2024. Baltimore, Md. Comment on evidence: In 2 brothers (P9A and P9B) with variable manifestations of autosomal recessive Bethlem myopathy-1C (BTHLM1C; 620726), Panades-de Oliveira et al. (2019) identified a homozygous c.7447A-G … (more) In 2 brothers (P9A and P9B) with variable manifestations of autosomal recessive Bethlem myopathy-1C (BTHLM1C; 620726), Panades-de Oliveira et al. (2019) identified a homozygous c.7447A-G transition (c.7447A-G, NM_004369.3) in exon 36 of the COL6A3 gene, resulting in a lys2483-to-glu (K2483E) substitution. (In the article by Panades-de Oliveira et al. (2019), this variant is incorrectly cited as lys2486-to-glu (K2486E) in the abstract and at various places in the text, but correctly as K2483E in Table 2 and at other places in the text.) Another patient (P8A) with the disorder was compound heterozygous for K2483E and a 1-bp deletion (c.8540delA; 120250.0013) in exon 39, predicted to result in a frameshift and premature termination. The mutations were found by next-generation sequencing and confirmed by Sanger sequencing. Functional studies of the variants and studies of patient cells were not performed. P9A, a 42-year-old man, had onset of proximal muscle weakness in childhood, whereas his brother (P9B) was almost asymptomatic at 48 years of age, except for hyperCKemia and distal contractures. In 16 patients from 14 families with autosomal recessive Bethlem myopathy-1C (BTHLM1C; 620726), Villar-Quiles et al. (2021) identified a c.7447A-G transition in the COL6A3 gene, resulting in a lys2483-to-glu (K2483E) substitution in a nonhelical domain. Twelve patients carried the variant in compound heterozygosity with another putative loss-of-function variant in the COL6A3 gene (see, e.g., R1597X, 120250.0014), whereas 4 patients (P11, P12, P13, and P14) were homozygous for the K2483E variant. Segregation studies performed in 8 families confirmed that the tested parents were unaffected heterozygous carriers. Fibroblasts derived from 5 of the compound heterozygous patients showed reduced collagen VI secretion, which was most likely due to the second loss-of-function COL6A3 variant. In contrast, fibroblasts from 3 patients who were homozygous for the K2483E variant showed essentially normal collagen VI secretion in 2 and mildly reduced secretion in 1, suggesting that the missense variant does not significantly impact COL6 assembly and secretion. Villar-Quiles et al. (2021) suggested that this missense variant may act as a modulator of the clinical phenotype. The 12 patients who were compound heterozygous for K2483E and another COL6A3 variant tended to present in childhood with proximal muscle weakness, joint contractures, and variable presence of rigid spine, skin abnormalities, and mild respiratory involvement. In contrast, the patients who were homozygous for the K2483E variant had fewer joint contractures, and none had distal hyperlaxity, skin abnormalities, or respiratory involvement. Hamosh (2024) noted that the K2483E variant was present in heterozygous state in 1,158 of 1,614,090 alleles in gnomAD (v4.1.0) and in 1 homozygote (frequency of 7.0 x 10(-4)). (less)
Pathogenic (Sep 04, 2024)	no assertion criteria provided Method: clinical testing	COL6A3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004104265.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Uncertain significance (-)	Flagged submission flagged submission Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807700.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Uncertain significance (-)	Flagged submission flagged submission Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920503.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

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.

Comment:

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.

Comment:

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

Comment:

Reported previously 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, 38155714); 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: 35239206, 26247046, 20576434, 28688748, 29970176, 20976770, 34426522, 33726816, 33596003, 33749658, 32528171, 30487145, 32448721, 32403337, 30564623, 37470033, 36779064, 30706156, 34720847, 37526466, 38127101, 38155714, 36964972, 33441455, 37273706)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinico-genetic spectrum of limb-girdle muscular weakness in Austria: A multicentre cohort study.	Krenn M	European journal of neurology	2022	PMID: 35239206
Clinical and Molecular Spectrum Associated with COL6A3 c.7447A>G p.(Lys2483Glu) Variant: Elucidating its Role in Collagen VI-related Myopathies.	Villar-Quiles RN	Journal of neuromuscular diseases	2021	PMID: 33749658
Collagen VI-Related Myopathy Caused by Compound Heterozygous Mutations of COL6A3 in a Consanguineous Kurdish Family.	Mihaylova V	Journal of clinical neuromuscular disease	2021	PMID: 33596003
Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.	Töpf A	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32528171
Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity.	Stavusis J	Neuromuscular disorders : NMD	2020	PMID: 32448721
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.	Gonzalez-Quereda L	Genes	2020	PMID: 32403337
Bethlem myopathy: a series of 16 patients and description of seven new associated mutations.	Panadés-de Oliveira L	Journal of neurology	2019	PMID: 30706156
Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.	Nallamilli BRR	Annals of clinical and translational neurology	2018	PMID: 30564623
Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients.	Fichna JP	Human genomics	2018	PMID: 29970176
Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period.	Sframeli M	Neuromuscular disorders : NMD	2017	PMID: 28688748
Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.	Hunter JM	Molecular genetics & genomic medicine	2015	PMID: 26247046
Early onset collagen VI myopathies: Genetic and clinical correlations.	Briñas L	Annals of neurology	2010	PMID: 20976770
Hamosh, A. Personal Communication. 2024. Baltimore, Md.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3	-	-	-	-
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Text-mined citations for rs139260335 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_004369.4(COL6A3):c.7447A>G (p.Lys2483Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139260335 ...