Submissions for variant NM_000397.4(CYBB):c.169G>T (p.Ala57Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003084665	SCV003479237	likely pathogenic	Granulomatous disease, chronic, X-linked	2022-08-31	criteria provided, single submitter	clinical testing	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 CYBB protein function. This variant has not been reported in the literature in individuals affected with CYBB-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 57 of the CYBB protein (p.Ala57Ser). 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.Ala57 amino acid residue in CYBB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8101486, 10914676, 21659519, 30470980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690365	SCV005184435	uncertain significance	not specified	2024-05-29	criteria provided, single submitter	clinical testing	Variant summary: CYBB c.169G>T (p.Ala57Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182736 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.169G>T in individuals affected with X-Linked Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2166020). Based on the evidence outlined above, the variant was classified as uncertain significance.