Submissions for variant NM_001379500.1(COL18A1):c.743C>T (p.Ser248Phe)

gnomAD frequency: 0.00053  dbSNP: rs200073359

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000324509	SCV000436360	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	RCV001339486	SCV001533235	uncertain significance	not provided	2025-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 248 of the COL18A1 protein (p.Ser248Phe). This variant is present in population databases (rs200073359, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. 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: 340203). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV002520037	SCV003675759	uncertain significance	Inborn genetic diseases	2022-09-05	criteria provided, single submitter	clinical testing	The c.743C>T (p.S248F) alteration is located in coding exon 5 of the COL18A1 gene. This alteration results from a C to T substitution at nucleotide position 743, causing the serine (S) at amino acid position 248 to be replaced by a phenylalanine (F). Based on data from the Genome Aggregation Database (gnomAD) database, the COL18A1 c.743C>T alteration was observed in 0.05% (143/261378) of total alleles studied, with a frequency of 0.1% (121/119162) in the European (non-Finnish) subpopulation. This amino acid position is highly conserved in available vertebrate species. The p.S248F alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004549783	SCV004114854	uncertain significance	COL18A1-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The COL18A1 c.1283C>T variant is predicted to result in the amino acid substitution p.Ser428Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-46895394-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.