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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 10, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000653528.2

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

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

Gene:

COL6A3:collagen type VI alpha 3 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.3

Genomic location:

Preferred name:

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

HGVS:

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:

G1458R

Links:

dbSNP: rs397515332

NCBI 1000 Genomes Browser:

rs397515332

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]

Condition(s)

Name:: Bethlem myopathy 1A
Synonyms:: Myopathy, benign congenital, with contractures; Bethlem myopathy 1
Identifiers:: MONDO: MONDO:0024530; MedGen: CN029274; Orphanet: 610; OMIM: 158810

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000775409	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 10, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7695699, 24038877, 19344236, 27447704, 18825676, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000775409

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 10, 2018)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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]

PMID:: 7695699

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]

PMID:: 24038877
PMCID:: PMC4520221

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000775409.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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