rs886038925

Positions:

• chr2-189008117-GT-AA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3 PP5_Moderate

The NM_000090.4(COL3A1):​c.3500_3501delGTinsAA​(p.Gly1167Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1167D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189008117-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ: 4.0879 (greater than the threshold 3.09). Trascript score misZ: 4.5995 (greater than threshold 3.09). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. GenCC has associacion of the gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-189008117-GT-AA is Pathogenic according to our data. Variant chr2-189008117-GT-AA is described in ClinVar as [Pathogenic]. Clinvar id is 263793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.3500_3501delGTinsAA	p.Gly1167Glu	missense_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.3500_3501delGTinsAA	p.Gly1167Glu	missense_variant		1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.3401_3402delGTinsAA	p.Gly1134Glu	missense_variant		1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2014

The p.G1167E pathogenic mutation (also known as c.3500_3501delGTinsAA) is located in coding exon 47 of the COL3A1 gene. This alteration results from a deletion of GT and insertion of AA at nucleotide positions 3500-3501. The glycine at codon 1167 is replaced by glutamic acid. This amino acid position is highly conserved on sequence alignment. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286). In addition, another alteration of the same codon, p.G1167V (c.3500G>T), has been reported as pathogenic (Johnson PH et al. Hum Mutat. 1995;6(4):336-342). The p.G1167E alteration was likely the result of a de novo event in one proband tested by our laboratory; however, parental germline mosaicism cannot be ruled out. Based on the supporting evidence, p.G1167E is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886038925; hg19: chr2-189872843;