NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu) AND Ehlers-Danlos syndrome, type 4

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000475974.11

Allele description [Variation Report for NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)]

NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu)

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.4295G>T (p.Arg1432Leu)

HGVS:

NC_000002.12:g.189011668G>T
NG_007404.1:g.42296G>T
NM_000090.4:c.4295G>TMANE SELECT
NP_000081.1:p.Arg1432Leu
NP_000081.2:p.Arg1432Leu
LRG_3t1:c.4295G>T
LRG_3:g.42296G>T
LRG_3p1:p.Arg1432Leu
NC_000002.11:g.189876394G>T
NM_000090.3:c.4295G>T

Protein change:

R1432L

Links:

dbSNP: rs772428340

NCBI 1000 Genomes Browser:

rs772428340

Molecular consequence:

NM_000090.4:c.4295G>T - 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
SCV000541792	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25846194, 33125268, 28492532
SCV001423384	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV004828275	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 14, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25846194, 31075413, 33125268, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000541792

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 29, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001423384

GenomeConnect, ClinGen

no classification provided

not provided

unknown

phenotyping only

SCV004828275

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 14, 2024)

germline

clinical testing

PubMed (4)
[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	unknown	12	not provided	not provided	143475	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Clinical, structural, biochemical and X-ray crystallographic correlates of pathogenicity for variants in the C-propeptide region of the COL3A1 gene.

Stembridge NS, Vandersteen AM, Ghali N, Sawle P, Nesbitt M, Pollitt RC, Ferguson DJ, Holden S, Elmslie F, Henderson A, Hulmes DJ, Pope FM.

Am J Med Genet A. 2015 Aug;167A(8):1763-72. doi: 10.1002/ajmg.a.37081. Epub 2015 Apr 5.

PubMed [citation]

PMID:: 25846194

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000541792.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1432 of the COL3A1 protein (p.Arg1432Leu). This variant is present in population databases (rs772428340, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 25846194, 33125268; internal data). ClinVar contains an entry for this variant (Variation ID: 404289). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 GenomeConnect, ClinGen, SCV001423384.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpretted as Uncertain significance and reported on 02-03-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From All of Us Research Program, National Institutes of Health, SCV004828275.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with leucine at codon 1432 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with two siblings with Ehlers-Danlos-like symptoms without the vascular impairments typical of vascular Ehlers-Danlos (PMID: 25846194, 31075413) and in one individual affected with spontaneous coronary artery dissection (PMID: 33125268). This variant has been identified in 5/251334 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	143475	not provided	not provided		12	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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