Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000169578 | SCV000221081 | likely pathogenic | Niemann-Pick disease, type A | 2015-01-23 | criteria provided, single submitter | literature only | |
| Invitae | RCV001220627 | SCV001392630 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser174Leufs*19) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is present in population databases (rs786204733, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type A (PMID: 15221801). This variant is also known as c.512_513dupT p.F171fsX19. ClinVar contains an entry for this variant (Variation ID: 189153). For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV001248976 | SCV001422817 | likely pathogenic | Sphingomyelin/cholesterol lipidosis | 2020-01-22 | criteria provided, single submitter | curation | The p.Ser174LeufsTer19 variant in SMPD1 (also known as p.Ser172LeufsTer19 due to a difference in cDNA numbering) has been reported in one individual with Niemann-Pick disease (PMID: 15221801) and has been identified in 0.001% (1/111376) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs786204733). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 189153) as likely pathogenic by Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 174 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015). |
| Diagnostics Division, |
RCV000169578 | SCV001738445 | pathogenic | Niemann-Pick disease, type A | 2021-04-25 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000169578 | SCV002548081 | pathogenic | Niemann-Pick disease, type A | 2022-05-13 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.518dupT (p.Ser174LeufsX19) 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 allele was found at a frequency of 4e-06 in 247298 control chromosomes. c.518dupT has been reported in the literature in individuals affected with Niemann-Pick Disease Type A. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000169578 | SCV004205510 | pathogenic | Niemann-Pick disease, type A | 2023-04-22 | criteria provided, single submitter | clinical testing |