NM_000090.4(COL3A1):c.665G>A (p.Gly222Asp) AND Ehlers-Danlos syndrome, type 4

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 2, 2020
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:: RCV000087631.3

Allele description [Variation Report for NM_000090.4(COL3A1):c.665G>A (p.Gly222Asp)]

NM_000090.4(COL3A1):c.665G>A (p.Gly222Asp)

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.665G>A (p.Gly222Asp)

HGVS:

NC_000002.12:g.188989424G>A
NG_007404.1:g.20052G>A
NM_000090.4:c.665G>AMANE SELECT
NP_000081.1:p.Gly222Asp
NP_000081.2:p.Gly222Asp
LRG_3t1:c.665G>A
LRG_3:g.20052G>A
LRG_3p1:p.Gly222Asp
NC_000002.11:g.189854150G>A
NM_000090.3:c.665G>A

Links:

dbSNP: rs587779518

NCBI 1000 Genomes Browser:

rs587779518

Molecular consequence:

NM_000090.4:c.665G>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
SCV000120522	Collagen Diagnostic Laboratory, University of Washington	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV005398457	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 2, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21637106, 22492385, 29346445, 29940997, 30474650, 2934645, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000120522

Collagen Diagnostic Laboratory, University of Washington

no assertion criteria provided

Pathogenic

germline

clinical testing

SCV005398457

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 2, 2020)

germline

clinical testing

PubMed (7)
[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	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy.

Leistritz DF, Pepin MG, Schwarze U, Byers PH.

Genet Med. 2011 Aug;13(8):717-22. doi: 10.1097/GIM.0b013e3182180c89.

PubMed [citation]

PMID:: 21637106

Oral phenotype and scoring of vascular Ehlers-Danlos syndrome: a case-control study.

Ferré FC, Frank M, Gogly B, Golmard L, Naveau A, Chérifi H, Emmerich J, Gaultier F, Berdal A, Jeunemaitre X, Fournier BP.

BMJ Open. 2012 Apr 5;2(2):e000705. doi: 10.1136/bmjopen-2011-000705. Print 2012.

PubMed [citation]

PMID:: 22492385
PMCID:: PMC3323826

See all PubMed Citations (7)

Details of each submission

From Collagen Diagnostic Laboratory, University of Washington, SCV000120522.1

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398457.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with vascular Ehlers-Danlos syndrome. Haploinsufficiency as a result of null alleles appears to confer delayed onset, and milder clinical course (PMID: 2934645; 21637106). Dominant-negative as a result of missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region (PMID: 2934645). (I) 0108 - This gene is associated with both recessive and dominant disease. Vascular Ehlers-Danlos syndrome (EDS), AD; Polymicrogyria with or without vascular EDS, AR (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid (exon 8). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. (SP) 0601 - Variant is located in the well-established functional collagen triple helix domain and affecting the glycine of the G-X-Y repeats (PDB). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported in patients with vascular Ehlers-Danlos syndrome (ClinVar, PMID: 22492385, 29940997, 30474650). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Nov 24, 2024

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