rs587779451

Positions:

• chr2-188988106-CT-C

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.555del​(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.810

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.555del	p.Gly186ValfsTer36	frameshift_variant	6/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.555del	p.Gly186ValfsTer36	frameshift_variant	6/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.555del	p.Gly186ValfsTer36	frameshift_variant	6/50	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460788 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726696

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2017	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). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Ehlers-Danlos syndrome, type 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs587779451; hg19: chr2-189852832;