VCV000065410.54 - ClinVar

NM_001379500.1(COL18A1):c.3523_3524del (p.Leu1175fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(18)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001379500.1(COL18A1):c.3523_3524del (p.Leu1175fs)

Variation ID: 65410 Accession: VCV000065410.54

Type and length

Deletion, 2 bp

Location

Cytogenetic: 21q22.3 21: 45510091-45510092 (GRCh38) [ NCBI UCSC ] 21: 46930005-46930006 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 23, 2015	Oct 20, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001379500.1:c.3523_3524del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001366429.1:p.Leu1175fs	frameshift
NM_001379500.1:c.3523_3524delCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_030582.4:c.4054_4055del	NP_085059.2:p.Leu1352fs	frameshift
NM_030582.4:c.4054_4055delCT
NM_130444.3:c.4759_4760del	NP_569711.2:p.Leu1587fs	frameshift
NC_000021.9:g.45510091_45510092del
NC_000021.8:g.46930005_46930006del
NG_011903.1:g.109900_109901del
NG_028278.2:g.58052_58053del

... more HGVS ... less HGVS

Protein change

L1352fs, L1587fs, L1175fs

Other names

NM_130445.2:c.3514_3515delCT
NM_130445.3:c.3514_3515del
NM_130445.4:c.3514_3515del

Canonical SPDI

NC_000021.9:45510090:CT:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00028

The Genome Aggregation Database (gnomAD) 0.00029

The Genome Aggregation Database (gnomAD), exomes 0.00030

Exome Aggregation Consortium (ExAC) 0.00089

Links

ClinGen: CA144775 OMIM: 120328.0002 OMIM: 120328.0008 dbSNP: rs398122391 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL18A1		-	-	GRCh38 GRCh38 GRCh37	1841	3025
SLC19A1		-	-	GRCh38 GRCh38 GRCh37	156	1240

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Knobloch syndrome	Pathogenic (3)	criteria provided, single submitter	Mar 5, 2022	RCV000055632.40
not provided	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000479282.41
Retinitis pigmentosa	Likely pathogenic (1)	no assertion criteria provided	Jan 1, 2015	RCV000505165.3
Macular dystrophy	Likely pathogenic (1)	no assertion criteria provided	Jan 1, 2015	RCV000504900.3
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Sep 15, 2017	RCV001074487.4
Glaucoma, primary closed-angle	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2016	RCV001198207.4
Glaucoma, primary closed-angle Knobloch syndrome 1	Pathogenic (1)	criteria provided, single submitter	Mar 29, 2022	RCV002504954.2
Knobloch syndrome 1	Pathogenic (1)	criteria provided, single submitter	May 4, 2023	RCV003235024.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 15, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240074.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma, primary closed-angle Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369077.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic.
Pathogenic (Apr 18, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064455.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Pathogenic (Mar 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051613.2 First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022	Comment: PVS1, PM2, PM3
Pathogenic (May 04, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Knobloch syndrome 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003934783.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023	Publications: PubMed (1) PubMed: 34828430 Comment: 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 … (more) 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. (less)
Pathogenic (Jun 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199173.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447309.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Retinal dystrophy (present) , Muscle weakness (present) , Global developmental delay (present) Sex: male
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Knobloch syndrome 1 Affected status: yes Allele origin: germline	DASA Accession: SCV002107162.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (4) PubMed: 29977801‚ 21862674‚ 23667181‚ 19390655 Comment: The c.4054_4055delCT;p.(Leu1355Valfs72) is a null frameshift variant (NMD) in the COL18A1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more) The c.4054_4055delCT;p.(Leu1355Valfs72) 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. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Mar 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Knobloch syndrome 1 Glaucoma, primary closed-angle Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812897.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567322.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001416967.4 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 12415512‚ 25456301‚ 19390655‚ 21862674‚ 23667181‚ 29977801 Comment: This sequence change creates a premature translational stop signal (p.Leu1172Valfs72) in the COL18A1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Leu1172Valfs72) 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. (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001501806.23 First in ClinVar: Mar 12, 2021 Last updated: Oct 20, 2024	Comment: COL18A1: PVS1, PM2, PM3 Number of individuals with the variant: 6
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598897.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 28041643 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Macular dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598896.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (1) PubMed: 28041643 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Pathogenic (Dec 13, 2017)	no assertion criteria provided Method: research	Knobloch syndrome Affected status: yes Allele origin: inherited	Molecular Genetics Laboratory, Institute for Ophthalmic Research Accession: SCV000924662.1 First in ClinVar: Jun 28, 2019 Last updated: Jun 28, 2019
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952203.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973916.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Nov 01, 2010)	no assertion criteria provided Method: literature only	KNOBLOCH SYNDROME 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000038936.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 03, 2022	Publications: PubMed (3) PubMed: 12415512‚ 19160445‚ 20799329 Comment on evidence: Suzuki et al. (2002) reported genotyping studies of 3 unrelated patients with Knobloch syndrome (KNO1; 267750) who were compound heterozygotes for a 2-bp deletion (3514_3515delCT) … (more) Suzuki et al. (2002) reported genotyping studies of 3 unrelated patients with Knobloch syndrome (KNO1; 267750) who were compound heterozygotes for a 2-bp deletion (3514_3515delCT) in exon 41 of the COL18A1 gene, each in combination with a different mutant companion allele. The 2-bp deletion was on the paternal allele in 2 cases and on the maternal allele in the third. A different haplotype was associated with this common pathogenic allele, suggesting that the mutation had originated more than once. Two of these patients had an encephalocele that had been resected; the third had a bone defect visualized by CT scan. All 3 had myopia and vitreoretinal degeneration and 2 had had retinal detachment. One of the patients, aged 21 years, had been blind from the age of 5. Paisan-Ruiz et al. (2009) reported 2 sisters from a small village in northern India who were homozygous for the 3514_3515delCT mutation. They had a complex neurologic disorder, including cognitive decline beginning around age 3 years, seizures, and adult-onset of progressive visual problems and cerebellar ataxia. The 48-year-old proband had glaucoma, lens dislocation, and retinal and corneal dystrophy. Cerebellar ataxia affected both upper and lower limbs, and she had nystagmus. She was independent for toileting and dressing. Brain MRI showed frontal polymicrogyria with severe cerebral and cerebellar atrophy. Her sister had a similar disease course. The 2-bp deletion occurred at nucleotide 3514 in isoform 2 and at nucleotide 4054 in isoform 1, resulting in frameshifts of both isoforms. Paisan-Ruiz et al. (2009) noted the expanding phenotypic variability associated with this mutation and with Knobloch syndrome. Mahajan et al. (2010) reported 2 sisters, born of unrelated El Salvadorian parents, with Knobloch syndrome who were homozygous for the 3514delCT deletion. In addition to the occipital defect and classic ophthalmologic findings in both girls, 1 developed acute lymphoblastic leukemia (ALL), pre-B type, at age 4 years. Mahajan et al. (2010) speculated that lack of endostatin in these patients, resulting from the deletion, may have contributed to the development of ALL in 1 of the girls. (less)
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes.	Villanueva-Mendoza C	Genes	2021	PMID: 34828430
Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree.	Zhang LS	International journal of ophthalmology	2018	PMID: 29977801
Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations.	Caglayan AO	Pediatric neurology	2014	PMID: 25456301
No evidence for locus heterogeneity in Knobloch syndrome.	Aldahmesh MA	Journal of medical genetics	2013	PMID: 23667181
Identification of ADAMTS18 as a gene mutated in Knobloch syndrome.	Aldahmesh MA	Journal of medical genetics	2011	PMID: 21862674
Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia.	Mahajan VB	American journal of medical genetics. Part A	2010	PMID: 20799329
Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome.	Suzuki O	Molecular vision	2009	PMID: 19390655
Homozygosity mapping through whole genome analysis identifies a COL18A1 mutation in an Indian family presenting with an autosomal recessive neurological disorder.	Paisán-Ruiz C	American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics	2009	PMID: 19160445
Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome.	Suzuki OT	American journal of human genetics	2002	PMID: 12415512

Text-mined citations for rs398122391 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001379500.1(COL18A1):c.3523_3524del (p.Leu1175fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398122391 ...