Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000410839 | SCV000485833 | likely pathogenic | Niemann-Pick disease, type A | 2016-02-18 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003114524 | SCV003800816 | likely pathogenic | Sphingomyelin/cholesterol lipidosis | 2023-01-06 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.1518C>G (p.Tyr506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251394 control chromosomes. To our knowledge, no occurrence of c.1518C>G in individuals affected with Niemann-Pick Disease and no experimental evidence demonstrating its impact on protein function have been reported. However c.1518C>A, which also results in a p.Tyr506X stop-gain, was reported in a homozygous individual with Niemann-Pick disease (PMID: 34273913). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000410839 | SCV004203225 | likely pathogenic | Niemann-Pick disease, type A | 2023-08-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003766123 | SCV004584799 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-09-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr506*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the SMPD1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 370493). This variant disrupts a region of the SMPD1 protein in which other variant(s) (p.His516Arg) have been determined to be pathogenic (PMID: 31122880, 33675270; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |