NM_001848.3(COL6A1):c.1945G>A (p.Glu649Lys) AND Bethlem myopathy 1

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Dec 17, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000626107.3

Allele description [Variation Report for NM_001848.3(COL6A1):c.1945G>A (p.Glu649Lys)]

NM_001848.3(COL6A1):c.1945G>A (p.Glu649Lys)

Gene:
COL6A1:collagen type VI alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.3
Genomic location:
Preferred name:
NM_001848.3(COL6A1):c.1945G>A (p.Glu649Lys)
HGVS:
  • NC_000021.9:g.46001375G>A
  • NG_008674.1:g.24627G>A
  • NM_001848.2:c.1945G>A
  • NM_001848.3:c.1945G>AMANE SELECT
  • NP_001839.2:p.Glu649Lys
  • NP_001839.2:p.Glu649Lys
  • LRG_475t1:c.1945G>A
  • LRG_475:g.24627G>A
  • LRG_475p1:p.Glu649Lys
  • NC_000021.8:g.47421289G>A
Protein change:
E649K
Links:
dbSNP: rs764129993
NCBI 1000 Genomes Browser:
rs764129993
Molecular consequence:
  • NM_001848.2:c.1945G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001848.3:c.1945G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Bethlem myopathy 1 (BTHLM1)
Synonyms:
Myopathy, benign congenital, with contractures; Muscular dystrophy, benign congenital; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 5
Identifiers:
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)
OriginMethodCitations
SCV000746734Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Likely pathogenic
(Dec 18, 2017)
inheritedclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000949659Invitaecriteria provided, single submitter
Uncertain significance
(Dec 17, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000746734.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000949659.1

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

Description

This sequence change replaces glutamic acid with lysine at codon 649 of the COL6A1 protein (p.Glu649Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs764129993, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL6A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 522912). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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

Last Updated: Nov 27, 2021

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