NM_004369.4(COL6A3):c.6193G>C (p.Gly2065Arg) AND Bethlem myopathy 1

Clinical significance:Pathogenic (Last evaluated: Jan 10, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_004369.4(COL6A3):c.6193G>C (p.Gly2065Arg)]

NM_004369.4(COL6A3):c.6193G>C (p.Gly2065Arg)

COL6A3:collagen type VI alpha 3 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_004369.4(COL6A3):c.6193G>C (p.Gly2065Arg)
  • NC_000002.12:g.237361138C>G
  • NG_008676.1:g.58070G>C
  • NM_004369.4:c.6193G>CMANE SELECT
  • NM_057166.5:c.4372G>C
  • NM_057167.4:c.5575G>C
  • NP_004360.2:p.Gly2065Arg
  • NP_004360.2:p.Gly2065Arg
  • NP_476507.3:p.Gly1458Arg
  • NP_476508.2:p.Gly1859Arg
  • LRG_473t1:c.6193G>C
  • LRG_473:g.58070G>C
  • LRG_473p1:p.Gly2065Arg
  • NC_000002.11:g.238269781C>G
  • NM_004369.3:c.6193G>C
Protein change:
dbSNP: rs397515332
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_004369.4:c.6193G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_057166.5:c.4372G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_057167.4:c.5575G>C - missense variant - [Sequence Ontology: SO:0001583]


Bethlem myopathy 1 (BTHLM1)
Myopathy, benign congenital, with contractures; Muscular dystrophy, benign congenital; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 5
MONDO: MONDO:0024530; MedGen: CN029274; Orphanet: 610; OMIM: 158810

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000775409Invitaecriteria provided, single submitter
(Jan 10, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J, Eaton M, Brodsky B, Berman HM.

Science. 1994 Oct 7;266(5182):75-81.

PubMed [citation]

Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies.

Butterfield RJ, Foley AR, Dastgir J, Asman S, Dunn DM, Zou Y, Hu Y, Donkervoort S, Flanigan KM, Swoboda KJ, Winder TL, Weiss RB, Bönnemann CG.

Hum Mutat. 2013 Nov;34(11):1558-67. doi: 10.1002/humu.22429.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000775409.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


This sequence change replaces glycine with arginine at codon 2065 of the COL6A3 protein (p.Gly2065Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 284796). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). A different missense substitution at this codon (p.Gly2065Asp) has been determined to be pathogenic (PMID: 18825676, 27447704). Glycine residues within the triple helix region are crucial to maintain fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL6A3, missense substitutions that affect glycine residues within the triplex helix domain have been reported in many patients affected with collagen VI myopathy (PMID: 24038877). For these reasons, this variant has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 8, 2022

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