Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| 3billion | RCV002052251 | SCV002318849 | uncertain significance | Niemann-Pick disease, type A | 2022-03-22 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SMPD1 related disorder (PMID:12369017). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.631>=0.6). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. |
| Labcorp Genetics |
RCV003773525 | SCV004570147 | uncertain significance | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 516 of the SMPD1 protein (p.His516Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 12369017). This variant is also known as H514Q. ClinVar contains an entry for this variant (Variation ID: 1526231). 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 SMPD1 protein function. This variant disrupts the p.His516 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31122880, 33675270). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |