NM_000090.4(COL3A1):c.709G>A (p.Gly237Arg) AND Ehlers-Danlos syndrome, type 4

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jul 25, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000087587.13

Allele description [Variation Report for NM_000090.4(COL3A1):c.709G>A (p.Gly237Arg)]

NM_000090.4(COL3A1):c.709G>A (p.Gly237Arg)

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.709G>A (p.Gly237Arg)

Other names:

p.G237R:GGA>AGA

HGVS:

NC_000002.12:g.188990114G>A
NG_007404.1:g.20742G>A
NM_000090.4:c.709G>AMANE SELECT
NP_000081.1:p.Gly237Arg
NP_000081.2:p.Gly237Arg
LRG_3t1:c.709G>A
LRG_3:g.20742G>A
LRG_3p1:p.Gly237Arg
NC_000002.11:g.189854840G>A
NM_000090.3:c.709G>A

Links:

dbSNP: rs587779625

NCBI 1000 Genomes Browser:

rs587779625

Molecular consequence:

NM_000090.4:c.709G>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
SCV000120477	Collagen Diagnostic Laboratory, University of Washington	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV000283467	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 25, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7695699, 8218237, 19344236, 25758994, 22019127, 24922459, 28492532
SCV000781226	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 1, 2016)	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

SCV000120477

Collagen Diagnostic Laboratory, University of Washington

no assertion criteria provided

Pathogenic

germline

clinical testing

SCV000283467

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 25, 2022)

germline

clinical testing

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

SCV000781226

Center for Human Genetics, Inc, Center for Human Genetics, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 1, 2016)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical 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 (8)

Details of each submission

From Collagen Diagnostic Laboratory, University of Washington, SCV000120477.1

#	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 Invitae, SCV000283467.9

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

Description

ClinVar contains an entry for this variant (Variation ID: 101349). For these reasons, this variant has been classified as Pathogenic. 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). 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. This missense change has been observed in individual(s) with vascular Ehlers‚ÄìDanlos syndrome (PMID: 22019127, 24922459). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 237 of the COL3A1 protein (p.Gly237Arg).

#	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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781226.1

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

#	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: May 1, 2024

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