Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000667895 | SCV000792408 | uncertain significance | Niemann-Pick disease, type A | 2017-06-22 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000734780 | SCV000862949 | uncertain significance | not provided | 2018-08-15 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000667895 | SCV001163660 | likely pathogenic | Niemann-Pick disease, type A | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001868217 | SCV002261681 | likely pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-12-22 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 178 of the SMPD1 protein (p.Ile178Asn). This variant is present in population databases (rs749780769, gnomAD 0.007%). This missense change has been observed in individual(s) with Niemann-Pick disease type B (PMID: 16472269). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.I176N. ClinVar contains an entry for this variant (Variation ID: 552601). 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 with a positive predictive value of 95%. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002233100 | SCV002511551 | uncertain significance | not specified | 2022-04-01 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.533T>A (p.Ile178Asn) results in a non-conservative amino acid change in the encoded protein sequence. It is also reported as p.Ile176Asn in the literature. Four of five in-silico tools predict a damaging effect of the variant on protein function. Based on crystal structure analysis, residue Ile176 is essential for stabilization of the proline rich linker in ASM metallophosphatase domain by hydrophobic interactions with alpha 5 and alpha 6 helices (Zhou_2016). The variant allele was found at a frequency of 3e-05 in 234460 control chromosomes. c.533T>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Niemann-Pick Disease (example, Mussig_2006, Harzer_2003). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=2; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |