Submissions for variant NM_001379500.1(COL18A1):c.107-12197G>A

gnomAD frequency: 0.00063  dbSNP: rs200284308

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517619	SCV000612884	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000766954	SCV000619522	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing	The R172H variant in the COL18A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is only present in a single alternate transcript of the COL18A1 gene (NM_030582.3), but not in any other known transcript, including the primary isoform used by the Human Gene Mutation database (NM_130445.3). Although not present in the homozygous state, the R172H variant is observed in 53/63514 (0.083%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The R172H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R172H as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000764262	SCV000895275	uncertain significance	Knobloch syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000766954	SCV001567957	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	The COL18A1 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_030582.4, and corresponds to NM_130445.2:c.107-12197G>A in the primary transcript. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 172 of the COL18A1 protein (p.Arg172His). This variant is present in population databases (rs200284308, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COL18A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447131). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002527466	SCV003713151	uncertain significance	Inborn genetic diseases	2021-08-10	criteria provided, single submitter	clinical testing	The c.515G>A (p.R172H) alteration is located in exon 1 (coding exon 1) of the COL18A1 gene. This alteration results from a G to A substitution at nucleotide position 515, causing the arginine (R) at amino acid position 172 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000766954	SCV004810471	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	COL18A1: BP4
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000766954	SCV001800148	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766954	SCV001969780	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004553126	SCV004722672	uncertain significance	COL18A1-related disorder	2024-07-09	no assertion criteria provided	clinical testing	The COL18A1 c.515G>A variant is predicted to result in the amino acid substitution p.Arg172His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.090% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too frequent for an unreported disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.