Submissions for variant NM_000088.4(COL1A1):c.3045+3G>A

gnomAD frequency: 0.00003  dbSNP: rs41316695

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537927	SCV000627220	uncertain significance	Osteogenesis imperfecta type I	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change falls in intron 41 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs41316695, gnomAD 0.05%), 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 COL1A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 456761). 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 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.
GeneDx	RCV001696985	SCV000720817	likely benign	not provided	2019-08-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002448622	SCV002753522	likely benign	Cardiovascular phenotype	2020-09-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230530	SCV003928662	benign	not specified	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: COL1A1 c.3045+3G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 250400 control chromosomes (gnomAD). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3045+3G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.