NM_000090.4(COL3A1):c.3103G>T (p.Gly1035Cys) AND Ehlers-Danlos syndrome, type 4

Clinical significance:Likely pathogenic (Last evaluated: Jan 1, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000087706.5

Allele description [Variation Report for NM_000090.4(COL3A1):c.3103G>T (p.Gly1035Cys)]

NM_000090.4(COL3A1):c.3103G>T (p.Gly1035Cys)

Gene:
COL3A1:collagen type III alpha 1 chain [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q32.2
Genomic location:
Preferred name:
NM_000090.4(COL3A1):c.3103G>T (p.Gly1035Cys)
HGVS:
  • NC_000002.12:g.189006354G>T
  • NG_007404.1:g.36982G>T
  • NM_000090.3:c.3103G>T
  • NM_000090.4:c.3103G>TMANE SELECT
  • NP_000081.1:p.Gly1035Cys
  • NP_000081.1:p.Gly1035Cys
  • NP_000081.2:p.Gly1035Cys
  • LRG_3t1:c.3103G>T
  • LRG_3:g.36982G>T
  • LRG_3p1:p.Gly1035Cys
  • NC_000002.11:g.189871080G>T
  • NC_000002.11:g.189871080G>T
  • P02461:p.Gly1035Cys
Links:
UniProtKB: P02461#VAR_011148; dbSNP: rs587779704
NCBI 1000 Genomes Browser:
rs587779704
Molecular consequence:
  • NM_000090.3:c.3103G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000090.4:c.3103G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Ehlers-Danlos syndrome, type 4 (EDSVASC)
Synonyms:
Ehlers-Danlos syndrome vascular type; Ehlers Danlos syndrome, ecchymotic type; Ehlers Danlos syndrome, arterial type; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0017314; MedGen: C0268338; Orphanet: 286; OMIM: 130050

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000120599Collagen Diagnostic Laboratory,University of Washingtonno assertion criteria providedPathogenicgermlineclinical testing

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

SCV000814816Invitaecriteria provided, single submitter
Likely pathogenic
(Jan 1, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

Pepin M, Schwarze U, Superti-Furga A, Byers PH.

N Engl J Med. 2000 Mar 9;342(10):673-80. Erratum in: N Engl J Med 2001 Feb 1;344(5):392.

PubMed [citation]
PMID:
10706896

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
See all PubMed Citations (7)

Details of each submission

From Collagen Diagnostic Laboratory,University of Washington, SCV000120599.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providedconfirm protein changenot providednot providednot providednot provided

From Invitae, SCV000814816.3

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

Description

This sequence change replaces glycine with cysteine at codon 1035 of the COL3A1 protein (p.Gly1035Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Ehlers–Danlos syndrome (PMID: 10706896). This variant is also known as G868C in the literature. ClinVar contains an entry for this variant (Variation ID: 101467). 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 C0). 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 COL3A1, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Oct 25, 2021

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