ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.320+1G>T

dbSNP: rs386833856
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000049825 SCV000220691 likely pathogenic GRACILE syndrome 2014-09-12 criteria provided, single submitter literature only
GeneDx RCV000489556 SCV000576973 likely pathogenic not provided 2019-10-17 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 12215968, 17314340, 25895478)
Illumina Laboratory Services, Illumina RCV004527276 SCV000914900 pathogenic Mitochondrial complex III deficiency nuclear type 1 2024-04-24 criteria provided, single submitter clinical testing
Invitae RCV000489556 SCV000939973 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the BCS1L gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs386833856, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) syndrome and Björnstad syndrome (PMID: 12215968, 17314340). This variant is also known as 321G>T and IVS2+1G>T. ClinVar contains an entry for this variant (Variation ID: 56412). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049825 SCV001362958 likely pathogenic GRACILE syndrome 2022-05-23 criteria provided, single submitter clinical testing Variant summary: BCS1L c.320+1G>T alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250504 control chromosomes. c.320+1G>T has been reported in the literature in individuals affected with GRACILE Syndrome (example, Visapaa_2002) and Bjornstad Syndrome (example, Hinson_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV002513688 SCV003681801 likely pathogenic Inborn genetic diseases 2020-11-05 criteria provided, single submitter clinical testing The c.320+1G>T intronic variant results from a G to T substitution one nucleotide after exon 3 (coding exon 1) of the BCS1L gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to disrupt the methionine residue at the initiation codon (ATG) or cause a shift in the mRNA reading frame; however, direct evidence is unavailable. This alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017), and would impact the first 120 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on data from the Genome Aggregation Database (gnomAD) database, the BCS1L c.320+1G>T alteration was observed in 0.0012% (3/250504) of total alleles studied. This alteration has been reported in an individual with GRACILE syndrome (Visapää, 2002) and in trans with another alteration in BCSL1 in an individual with Björnstad syndrome (Hinson, 2007). This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV003474632 SCV004210793 pathogenic Pili torti-deafness syndrome 2023-09-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000489556 SCV004238545 pathogenic not provided 2023-05-05 criteria provided, single submitter clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000049825 SCV000082234 probable-pathogenic GRACILE syndrome no assertion criteria provided not provided Converted during submission to Likely pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.