rs398122391

Positions:

• chr21-45510090-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001379500.1(COL18A1):​c.3523_3524delCT​(p.Leu1175fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,585,422 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 0.00029 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 3.46

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]

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

COL18A1 (HGNC:):

ACMG classification

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 21-45510090-CCT-C is Pathogenic according to our data. Variant chr21-45510090-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 65410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45510090-CCT-C is described in Lovd as [Pathogenic]. Variant chr21-45510090-CCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.3523_3524delCT	p.Leu1175fs	frameshift_variant	40/42	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.3523_3524delCT	p.Leu1175fs	frameshift_variant	40/42		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152204 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000303 AC: 59 AN: 194886 Hom.: 0 AF XY: 0.000361 AC XY: 39 AN XY: 108044

Gnomad AFR exome AF: 0.0000960

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.000265

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000480

Gnomad NFE exome AF: 0.000302

Gnomad OTH exome AF: 0.000785

GnomAD4 exome AF: 0.000309 AC: 443 AN: 1433100 Hom.: 0 AF XY: 0.000315 AC XY: 224 AN XY: 711400

Gnomad4 AFR exome AF: 0.000365

Gnomad4 AMR exome AF: 0.000261

Gnomad4 ASJ exome AF: 0.000117

Gnomad4 EAS exome AF: 0.000315

Gnomad4 SAS exome AF: 0.000289

Gnomad4 FIN exome AF: 0.000586

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.000354

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152322 Hom.: 0 Cov.: 34 AF XY: 0.000242 AC XY: 18 AN XY: 74486

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000276

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	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: 21937992, 28041643, 25456301, 23667181, 19160445, 20979194, 31415705, 12415512, 33238767, 31896775, 32178553, 28950998, 32581362, 29977801) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	COL18A1: PVS1, PM2, PM3 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Leu1172Valfs*72) 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). This variant is present in population databases (rs398122391, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with Knobloch syndrome (PMID: 19390655, 21862674, 23667181, 29977801). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu1587Valfs*72. ClinVar contains an entry for this variant (Variation ID: 65410). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 03, 2021	PVS1, PM2, PM3 -

Knobloch syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2010	- -
Pathogenic, no assertion criteria provided	research	Molecular Genetics Laboratory, Institute for Ophthalmic Research	Dec 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 05, 2022	The c.4054_4055delCT;p.(Leu1355Valfs*72) is a null frameshift variant (NMD) in the COL18A1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 65410; PMID: 29977801; PMID: 21862674; PMID: 23667181; PMID: 19390655) - PS4. The variant is present at low allele frequencies population databases (rs398122391 – gnomAD 0.002961%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Knobloch syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 04, 2023

Variant summary: COL18A1 c.3523_3524delCT (p.Leu1175ValfsX72) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0003 in 194886 control chromosomes. c.3523_3524delCT has been reported in the literature in individuals affected with Knobloch Syndrome 1 (example: Villanueva-Mendoza_2021). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34828430). 12 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=11) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Macular dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Glaucoma, primary closed-angle Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. -

Knobloch syndrome 1;C5394374:Glaucoma, primary closed-angle Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 15, 2017

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs398122391; hg19: chr21-46930004;