ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.325C>T (p.Arg109Trp)

gnomAD frequency: 0.00009  dbSNP: rs141257714
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000199842 SCV000251200 likely pathogenic not provided 2023-10-04 criteria provided, single submitter clinical testing Functional studies found R109W was unable to rescue oxidation phosphorylation phenotype of BSCIL deficient yeast cells (Olahova et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34662929, 31435670)
Invitae RCV000199842 SCV003299179 pathogenic not provided 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 109 of the BCS1L protein (p.Arg109Trp). This variant is present in population databases (rs141257714, gnomAD 0.03%). This missense change has been observed in individuals with BCS1L-related conditions (PMID: 31435670, 34662929). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214166). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCS1L protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BCS1L function (PMID: 31435670). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226245 SCV003922925 pathogenic GRACILE syndrome 2023-03-21 criteria provided, single submitter clinical testing Variant summary: BCS1L c.325C>T (p.Arg109Trp) results in a non-conservative amino acid change located in the BCS1, N-terminal domain (IPR014851) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251486 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BCS1L causing GRACILE Syndrome (4.4e-05 vs 0.00047), allowing no conclusion about variant significance. c.325C>T has been reported in the literature in at least three homozygous individuals, 2 of whom were siblings, affected with GRACILE Syndrome (Olahova_2019, Hikmat_2021). These data indicate that the variant is very likely to be associated with disease. Yeast complementation studies showed that the variant was not able to rescue oxidative phosphorylation in a BCS1L deficient yeast strain, indicating loss of function (Olahova_2019). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003474949 SCV004210797 likely pathogenic Pili torti-deafness syndrome 2023-08-30 criteria provided, single submitter clinical testing

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