Submissions for variant NM_001379500.1(COL18A1):c.2433G>A (p.Pro811=)

gnomAD frequency: 0.00007  dbSNP: rs200147240

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001142031	SCV001302426	uncertain significance	Knobloch syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858931	SCV002247101	uncertain significance	not provided	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change affects codon 811 of the COL18A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL18A1 protein. This variant also falls at the last nucleotide of exon 28, which is part of the consensus splice site for this exon. This variant is present in population databases (rs200147240, gnomAD 0.02%). 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: 898258). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV002559375	SCV003566115	uncertain significance	Inborn genetic diseases	2021-10-01	criteria provided, single submitter	clinical testing	Occurs in the last base pair of the exon Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.