NM_004369.4(COL6A3):c.6890G>C (p.Gly2297Ala) AND Bethlem myopathy 1

Clinical significance:Uncertain significance (Last evaluated: Sep 29, 2019)

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.6890G>C (p.Gly2297Ala)]

NM_004369.4(COL6A3):c.6890G>C (p.Gly2297Ala)

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.6890G>C (p.Gly2297Ala)
  • NC_000002.12:g.237348653C>G
  • NG_008676.1:g.70555G>C
  • NM_004369.3:c.6890G>C
  • NM_004369.4:c.6890G>CMANE SELECT
  • NM_057166.5:c.5069G>C
  • NM_057167.4:c.6272G>C
  • NP_004360.2:p.Gly2297Ala
  • NP_004360.2:p.Gly2297Ala
  • NP_476507.3:p.Gly1690Ala
  • NP_476508.2:p.Gly2091Ala
  • LRG_473t1:c.6890G>C
  • LRG_473:g.70555G>C
  • LRG_473p1:p.Gly2297Ala
  • NC_000002.11:g.238257296C>G
Protein change:
dbSNP: rs886043576
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_004369.3:c.6890G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004369.4:c.6890G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_057166.5:c.5069G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_057167.4:c.6272G>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)
SCV001378643Invitaecriteria provided, single submitter
Uncertain significance
(Sep 29, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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



Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients.

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M.

Ann Clin Transl Neurol. 2018 Dec;5(12):1574-1587. doi: 10.1002/acn3.649.

PubMed [citation]

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]
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001378643.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)


This sequence change replaces glycine with alanine at codon 2297 of the COL6A3 protein (p.Gly2297Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the heterozygous state in individuals affected with progressive limb-girdle muscular dystrophy; however, these individuals were also found to have a homozygous pathogenic variant in another gene (PMID: 30564623). ClinVar contains an entry for this variant (Variation ID: 287133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A3, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 15689448, 24038877) compared to the general population (ExAC). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 30, 2021

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