Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001980495 | SCV002273641 | likely pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2021-12-07 | 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.Pro477 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12556236, 12712061, 15221801, 17011332). 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 SMPD1 protein function. This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 477 of the SMPD1 protein (p.Pro477Gln). |
| Prevention |
RCV004729017 | SCV005336170 | uncertain significance | SMPD1-related disorder | 2024-03-08 | no assertion criteria provided | clinical testing | The SMPD1 c.1430C>A variant is predicted to result in the amino acid substitution p.Pro477Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. Alternate nucleotide substitutions affecting the same amino acid (p.Pro477Leu and p.Pro477Thr) have been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease (Table 1, Wasserstein et al. 2006. PubMed ID: 17011332; Table 1, Ranganath et al. 2016. PubMed ID: 27338287). Although we suspect the c.1430C>A (p.Pro477Gln) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |