Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000000408 | SCV004028593 | pathogenic | Combined deficiency of sialidase AND beta galactosidase | 2023-07-25 | criteria provided, single submitter | clinical testing | Variant summary: CTSA c.146A>G (p.Gln49Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249136 control chromosomes (gnomAD). c.146A>G has been reported in the literature in individuals affected with Galactosialidosis (Shimmoto_1993, Hossain_2016, Matsumoto_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that cells with the variant protein lacked carboxypeptidase, alpha-neuraminidase, and beta-galactosidase activity (Shimmoto_1993). The following publications have been ascertained in the context of this evaluation (PMID: 8514852, 26259553, 18396002). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV000000408 | SCV004298091 | likely pathogenic | Combined deficiency of sialidase AND beta galactosidase | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 67 of the CTSA protein (p.Gln67Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with galactosialidosis (PMID: 8514852, 18396002, 26259553). This variant is also known as Q49R. ClinVar contains an entry for this variant (Variation ID: 377). 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 CTSA protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CTSA function (PMID: 8514852). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| OMIM | RCV000000408 | SCV000020552 | pathogenic | Combined deficiency of sialidase AND beta galactosidase | 1993-06-01 | no assertion criteria provided | literature only |