rs587779585

Variant names:

• chr2-189011667-C-T
• rs587779585
• NM_000090.4:c.4294C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000090.4(COL3A1):​c.4294C>T​(p.Arg1432*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.83

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 Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0243 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-189011667-C-T is Pathogenic according to our data. Variant chr2-189011667-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101298.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr2-189011667-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.4294C>T	p.Arg1432*	stop_gained	Exon 51 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.4294C>T	p.Arg1432*	stop_gained	Exon 51 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.4195C>T	p.Arg1399*	stop_gained	Exon 50 of 50	1		ENSP00000415346.2
COL3A1	ENST00000487010.1	n.1673C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:2

Sep 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of Ehlers-Danlos syndrome, vascular type (PMID: 11577371; Invitae). ClinVar contains an entry for this variant (Variation ID: 101298). This variant disrupts a region of the COL3A1 protein in which other variant(s) (p.Pro1440Leu) have been observed in individuals with COL3A1-related conditions (PMID: 25846194). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change creates a premature translational stop signal (p.Arg1432*) in the COL3A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the COL3A1 protein. -

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Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

May 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 35 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; One study showed that p.(R143*) failed to participate in trimer formation, which reduced the amount of mature molecule produced (Schwarze et al., 2001); additional studies are needed to validate this effect in vivo; This variant is associated with the following publications: (PMID: 19455184, 11577371) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
Vest4		0.63
GERP RS		2.8

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: rs587779585; hg19: chr2-189876393; COSMIC: COSV58591606;