rs587779527

chr2-188997189-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000090.4(COL3A1):c.1786C>T(p.Arg596Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL3A1 NM_000090.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 2-188997189-C-T is Pathogenic according to our data. Variant chr2-188997189-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 242648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.1786C>T	p.Arg596Ter	stop_gained	25/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.1786C>T	p.Arg596Ter	stop_gained	25/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1687C>T	p.Arg563Ter	stop_gained	24/50	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 05, 2019	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jul 08, 2019	This variant is interpreted as a Pathogenic for Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PVS1, PP1. -

Ehlers-Danlos syndrome, type 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 242648). This premature translational stop signal has been observed in individual(s) with Ehlers-Danlos syndrome, vascular type (PMID: 25205403, 25758994). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg596*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2022

Identified in compound heterozygous state with a missense COL3A1 variant in two siblings with vEDS; however, family members who were only heterozygous for p.(R596*) had no major features of vEDS, indicating marked clinical variability (Pepin et al., 2014; Jorgensen et al., 2015); 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: 25205403, 28258187, 30474650, 24922459, 25758994) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		4.2

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

LitVar

Other links and lift over

dbSNP: rs587779527; hg19: chr2-189861915; COSMIC: COSV58590658; COSMIC: COSV58590658;