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GeneBe

rs886038925

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate

The NM_000090.4(COL3A1):​c.3500_3501delinsAA​(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. G1167V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL3A1
NM_000090.4 missense

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000090.4
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr2-189008117-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, COL3A1
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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 UniProt
COL3A1NM_000090.4 linkuse as main transcriptc.3500_3501delinsAA p.Gly1167Glu missense_variant 47/51 ENST00000304636.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL3A1ENST00000304636.9 linkuse as main transcriptc.3500_3501delinsAA p.Gly1167Glu missense_variant 47/511 NM_000090.4 P1P02461-1
COL3A1ENST00000450867.2 linkuse as main transcriptc.3401_3402delinsAA p.Gly1134Glu missense_variant 46/501

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 10, 2014The 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

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886038925; hg19: chr2-189872843; API