NM_000090.4(COL3A1):c.2222G>A (p.Gly741Asp) AND Ehlers-Danlos syndrome, type 4

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 17, 2019
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:: RCV000087343.3

Allele description [Variation Report for NM_000090.4(COL3A1):c.2222G>A (p.Gly741Asp)]

NM_000090.4(COL3A1):c.2222G>A (p.Gly741Asp)

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.2222G>A (p.Gly741Asp)

HGVS:

NC_000002.12:g.188999570G>A
NG_007404.1:g.30198G>A
NM_000090.4:c.2222G>AMANE SELECT
NP_000081.1:p.Gly741Asp
NP_000081.2:p.Gly741Asp
LRG_3t1:c.2222G>A
LRG_3:g.30198G>A
LRG_3p1:p.Gly741Asp
NC_000002.11:g.189864296G>A
NM_000090.3:c.2222G>A

Links:

dbSNP: rs553203474

NCBI 1000 Genomes Browser:

rs553203474

Molecular consequence:

NM_000090.4:c.2222G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000120223	Collagen Diagnostic Laboratory, University of Washington	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV004847685	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000120223

Collagen Diagnostic Laboratory, University of Washington

no assertion criteria provided

Pathogenic

germline

clinical testing

SCV004847685

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 17, 2019)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Details of each submission

From Collagen Diagnostic Laboratory, University of Washington, SCV000120223.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847685.1

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

Description

The p.Gly741Asp variant in COL3A1 has been identified in 2 individuals with vascular Ehlers Danlos syndrome (vEDS; Frank 2015, Pepin 2014) and was absent from large population studies. In addition, 2 other variants at the same position (p.Gly741Cys and p.Gly741Ser) have also been identified in individuals with vEDS (Inokuchi 2014, Frank 2015, Pepin 2014, ClinVar), suggesting changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the p.Gly741Asp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermore, this variant affects a highly conserved glycine (Gly) residue in the Gly-X-Y motif, which is a common finding in individuals with vEDS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant vascular Ehlers Danlos syndrome. ACMG/AMP Criteria applied: PM1; PM2; PM5; PP3; PS4_Supporting.

#	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: Jun 2, 2024

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