ClinVar Miner

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

dbSNP: rs386833856
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Total submissions: 6
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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 RCV000778593 SCV000914900 uncertain significance BCS1L-Related Disorders 2018-11-21 criteria provided, single submitter clinical testing The BCS1L c.320+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant is reported in one study and found in one individual with GRACILE syndrome in a compound heterozygous state along with an intronic variant upstream of the start codon (Visapaa et al. 2002). The variant was absent from 140 control individuals and is reported at a frequency of 0.000045 in the European (non-Finnish) population of the Exome Aggregation Consortium (Visapaa et al. 2002). Based on the potential impact of splice donor variants and the limited evidence, the c.320+1G>T variant is classified as a variant of unknown significance but suspicious for pathogenicity for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000489556 SCV000939973 pathogenic not provided 2021-12-17 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.
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.

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