NM_000090.4(COL3A1):c.4295G>T (p.Arg1432Leu) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 30, 2023
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:: RCV001188122.6

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]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001355095	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25846194, 31075413, 33125268, 25741868
SCV002629582	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 6, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25846194, 31075413 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001355095

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 30, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002629582

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 6, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

Carss KJ, Baranowska AA, Armisen J, Webb TR, Hamby SE, Premawardhana D, Al-Hussaini A, Wood A, Wang Q, Deevi SVV, Vitsios D, Lewis SH, Kotecha D, Bouatia-Naji N, Hesselson S, Iismaa SE, Tarr I, McGrath-Cadell L, Muller DW, Dunwoodie SL, Fatkin D, Graham RM, et al.

Circ Genom Precis Med. 2020 Dec;13(6):e003030. doi: 10.1161/CIRCGEN.120.003030. Epub 2020 Oct 30.

PubMed [citation]

PMID:: 33125268
PMCID:: PMC7748045

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

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001355095.3

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

From Ambry Genetics, SCV002629582.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R1432L variant (also known as c.4295G>T), located in coding exon 51 of the COL3A1 gene, results from a G to T substitution at nucleotide position 4295. The arginine at codon 1432 is replaced by leucine, an amino acid with dissimilar properties. This variant was detected in a proband and sibling with features of Ehlers-Danlos syndrome (EDS), but who were not reported to have arterial or organ fragility findings associated with vascular EDS (Stembridge NS et al. Am. J. Med. Genet. A, 2015 Aug;167A:1763-72). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 7, 2024

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