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NM_000090.4(COL3A1):c.2078G>C (p.Gly693Ala) AND Ehlers-Danlos syndrome, type 4

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Nov 14, 2023
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:
RCV000087366.10

Allele description [Variation Report for NM_000090.4(COL3A1):c.2078G>C (p.Gly693Ala)]

NM_000090.4(COL3A1):c.2078G>C (p.Gly693Ala)

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.2078G>C (p.Gly693Ala)
HGVS:
  • NC_000002.12:g.188999340G>C
  • NG_007404.1:g.29968G>C
  • NM_000090.4:c.2078G>CMANE SELECT
  • NP_000081.1:p.Gly693Ala
  • NP_000081.2:p.Gly693Ala
  • LRG_3t1:c.2078G>C
  • LRG_3:g.29968G>C
  • LRG_3p1:p.Gly693Ala
  • NC_000002.11:g.189864066G>C
  • NM_000090.3:c.2078G>C
Links:
dbSNP: rs587779442
NCBI 1000 Genomes Browser:
rs587779442
Molecular consequence:
  • NM_000090.4:c.2078G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Ehlers-Danlos syndrome, type 4
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
SCV000120248Collagen Diagnostic Laboratory, University of Washington
no assertion criteria provided
Pathogenicgermlineclinical testing

SCV001235557Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Nov 14, 2023)
germlineclinical testing

PubMed (6)
[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

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

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG, Braswell E, Zhu D, Apigo J, Baum J, Brodsky B.

Biochemistry. 1993 Nov 2;32(43):11688-95.

PubMed [citation]
PMID:
8218237
See all PubMed Citations (6)

Details of each submission

From Collagen Diagnostic Laboratory, University of Washington, SCV000120248.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providedconfirm protein changenot providednot providednot providednot provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001235557.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 693 of the COL3A1 protein (p.Gly693Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of vascular Ehlers-Danlos syndrome (PMID: 24922459). ClinVar contains an entry for this variant (Variation ID: 101129). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. 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, variants that affect 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: Sep 29, 2024