Submissions for variant NM_001079866.2(BCS1L):c.295C>T (p.Pro99Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002671772	SCV002993972	likely pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro99 amino acid residue in BCS1L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11528392, 17314340, 20518024, 24655110, 29090881). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with BCS1L-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 99 of the BCS1L protein (p.Pro99Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690314	SCV005185203	uncertain significance	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: BCS1L c.295C>T (p.Pro99Ser) results in a non-conservative amino acid change located in the BCS1, N-terminal domain (IPR014851) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.295C>T in individuals affected with GRACILE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1952511). Based on the evidence outlined above, the variant was classified as uncertain significance.