2-188992208-C-T

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.976C>T(p.Arg326*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). 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 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.55

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 2-188992208-C-T is Pathogenic according to our data. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188992208-C-T is described in CliVar as Pathogenic. Clinvar id is 101324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.976C>T	p.Arg326*	stop_gained	Exon 14 of 51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL3A1	ENST00000304636.9 link	c.976C>T	p.Arg326*	stop_gained	Exon 14 of 51	1	NM_000090.4	ENSP00000304408.4	P02461-1
COL3A1	ENST00000450867.2 link	c.976C>T	p.Arg326*	stop_gained	Exon 14 of 50	1		ENSP00000415346.2	H7C435
COL3A1	ENST00000713745.1 link	c.976C>T	p.Arg326*	stop_gained	Exon 14 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1 link	c.976C>T	p.Arg326*	stop_gained	Exon 14 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111918

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4

Pathogenic:2

Collagen Diagnostic Laboratory, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg326*) in the COL3A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Ehlers-Danlos syndrome, type IV (PMID: 24922459). ClinVar contains an entry for this variant (Variation ID: 101324). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Nov 04, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient belonging to a cohort of individuals with vascular Ehlers-Danlos syndrome in published literature (PMID: 24922459); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24922459) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.6

Vest4

0.89

ClinPred

0.98

GERP RS

6.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over