ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.340C>T (p.Arg114Trp)

gnomAD frequency: 0.00005  dbSNP: rs778769841
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001950896 SCV002235838 pathogenic not provided 2024-01-31 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 114 of the BCS1L protein (p.Arg114Trp). This variant is present in population databases (rs778769841, gnomAD 0.01%). This missense change has been observed in individual(s) with BCS1L-related conditions (PMID: 17314340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1455942). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BCS1L protein function. Experimental studies have shown that this missense change affects BCS1L function (PMID: 17314340). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002300634 SCV002598778 likely pathogenic Pili torti-deafness syndrome 2022-09-08 criteria provided, single submitter clinical testing Variant summary: BCS1L c.340C>T (p.Arg114Trp) results in a non-conservative amino acid change located in the BCS1, N-terminal domain (IPR014851) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251494 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BCS1L causing Bjornstad Syndrome (8.4e-05 vs 0.0035), allowing no conclusion about variant significance. c.340C>T has been reported in the literature in at least one family with siblings who were affected with Bjornstad Syndrome (Hinson_2007). These data indicate that the variant may be associated with disease. Experimental evidence using a yeast complementation assay with Bcs1-deficient yeast showed that the variant is incapable of rescuing growth on mitochondria selective growth media, with activity comparable to nonsense variants, indicating loss of function (Hinson_2007). One ClinVar submitter has assessed the variant since 2014: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV002300634 SCV004210783 likely pathogenic Pili torti-deafness syndrome 2024-03-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005016948 SCV005650499 likely pathogenic Pili torti-deafness syndrome; GRACILE syndrome; Mitochondrial complex III deficiency nuclear type 1 2024-06-01 criteria provided, single submitter clinical testing

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