Submissions for variant NM_001379500.1(COL18A1):c.2118dup (p.Gly707fs)

dbSNP: rs775168204

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000055633	SCV000247072	pathogenic	Knobloch syndrome	2015-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001561888	SCV001784570	pathogenic	not provided	2024-05-03	criteria provided, single submitter	clinical testing	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, 31725702)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001561888	SCV002232137	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335083	SCV004046303	pathogenic	COL18A1-related disorder		criteria provided, single submitter	clinical testing	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.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000055633	SCV005420651	pathogenic	Knobloch syndrome	2024-10-04	criteria provided, single submitter	research	PVS1(strong),PM2
OMIM	RCV000055633	SCV000083856	pathogenic	Knobloch syndrome	2013-08-01	no assertion criteria provided	literature only