rs775168204

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001379500.1(COL18A1):c.2118dup(p.Gly707ArgfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,611,426 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

COL18A1
NM_001379500.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -1.80

Variant links:

Genes affected

COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

COL18A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 21-45491268-G-GC is Pathogenic according to our data. Variant chr21-45491268-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 65411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL18A1	NM_001379500.1 linkuse as main transcript	c.2118dup	p.Gly707ArgfsTer23	frameshift_variant	22/42	ENST00000651438.1
COL18A1	NM_030582.4 linkuse as main transcript	c.2658dup	p.Gly887ArgfsTer23	frameshift_variant	21/41
COL18A1	NM_130444.3 linkuse as main transcript	c.3363dup	p.Gly1122ArgfsTer23	frameshift_variant	21/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1 linkuse as main transcript	c.2118dup	p.Gly707ArgfsTer23	frameshift_variant	22/42		NM_001379500.1		P39060-2
COL18A1	ENST00000355480.10 linkuse as main transcript	c.2658dup	p.Gly887ArgfsTer23	frameshift_variant	21/41	1			P39060-1
COL18A1	ENST00000342220.9 linkuse as main transcript	c.159dup	p.Gly54ArgfsTer23	frameshift_variant	3/23	2
COL18A1	ENST00000359759.8 linkuse as main transcript	c.3363dup	p.Gly1122ArgfsTer23	frameshift_variant	21/41	5		P1	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000286

AC:

AN:

244716

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

133868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.0000364

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1459384

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726042

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000384

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	Frameshift 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: 23667181) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change creates a premature translational stop signal (p.Gly707Argfs*23) in the COL18A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL18A1 are known to be pathogenic (PMID: 12415512, 25456301). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Knobloch syndrome (PMID: 23667181). ClinVar contains an entry for this variant (Variation ID: 65411). For these reasons, this variant has been classified as Pathogenic. -

Knobloch syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -

COL18A1-related disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This frameshifting variant in exon 21 of 41 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported, named as c.2118dup (p.Gly707fs) on transcript NM_001379500.1, as a compound heterozygous change with a frameshift variant in patients with Knobloch Syndrome (PMID: 23667181). The c.2658dup (p.Gly887ArgfsTer23) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (7/244716) and is absent in the homozygous state, thus is presumed to be rare. Loss-of-function variation in COL18A1 is an established mechanism of disease (PMID: 27746220). Based on the available evidence, the c.2658dup (p.Gly887ArgfsTer23) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over