2-188988106-CT-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000090.4(COL3A1):c.555delT(p.Gly186ValfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P185P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.810

Publications

3 publications found

Variant links:

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

COL3A1 Gene-Disease associations (from GenCC):

autosomal dominant Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

COL3A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-188988106-CT-C is Pathogenic according to our data. Variant chr2-188988106-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 101141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.555delT	p.Gly186ValfsTer36	frameshift	Exon 6 of 51	NP_000081.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.555delT	p.Gly186ValfsTer36	frameshift	Exon 6 of 51	ENSP00000304408.4
COL3A1	ENST00000450867.2	TSL:1	c.555delT	p.Gly186ValfsTer36	frameshift	Exon 6 of 50	ENSP00000415346.2
COL3A1	ENST00000713745.1		c.555delT	p.Gly186ValfsTer36	frameshift	Exon 6 of 49	ENSP00000519049.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111200

Other (OTH)

AF:

0.00

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 01, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.555delT pathogenic variant in the COL3A1 gene has previously been reported in one individual with soft, velvety, translucent skin with atrophic scars, as well as multiple dissections involving the splenic and hepatic branches of the celiac artery and both renal arteries (Schwarze et al., 2001; Leistritz et al., 2011). This variant causes a shift in reading frame starting at codon glycine 186, changing it to a valine, and creating a premature stop codon at position 36 of the new reading frame, denoted p.Gly186ValfsX36. Moreover, mRNA studies demonstrated that c.555delT leads to the incorporation of a premature termination codon resulting in an unstable mRNA product that is rapidly degraded (Schwarze et al., 2001). Other downstream frameshift variants in the COL3A1 gene have been reported in HGMD in association with EDS type IV (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.555delT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Ehlers-Danlos syndrome, type 4

Pathogenic:2

Jan 02, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Collagen Diagnostic Laboratory, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Aug 06, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.555delT pathogenic mutation, located in coding exon 6 of the COL3A1 gene, results from a deletion of one nucleotide at nucleotide position 555, causing a translational frameshift with a predicted alternate stop codon (p.G186Vfs*36). This variant was reported in individual(s) with features consistent with COL3A1-related Ehlers-Danlos syndrome (Schwarze U et al. Am J Hum Genet, 2001 Nov;69:989-1001; Leistritz DF et al. Genet Med, 2011 Aug;13:717-22; Shalhub S et al. J Vasc Surg Cases Innov Tech, 2023 Jun;9:101192; Demirdas S et al. Circ Genom Precis Med, 2024 Jun;17:e003978; Liu H et al. J Vasc Surg, 2025 Mar;81:557-565.e7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Cardiovascular phenotype

Pathogenic:1

Jun 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PS4_supp

Aortic dissection

Pathogenic:1

May 14, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG-criteria applied: PVS1, PS3_Supporting, PS4_Moderate, PM2

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.81

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over