Total submissions: 12
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000193674 | SCV000248992 | pathogenic | Niemann-Pick disease, type A | 2015-01-21 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000372224 | SCV000329525 | pathogenic | not provided | 2023-03-25 | criteria provided, single submitter | clinical testing | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 32292456, 26499107, 23770607, 12607113, 21502868, 26169295, 27338287, 22796693, 23415435, 19405096, 17011332, 8680412) |
| Counsyl | RCV000193674 | SCV000486403 | pathogenic | Niemann-Pick disease, type A | 2016-05-24 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000634567 | SCV000755897 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg443*) 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 (rs120074127, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type A and B (PMID: 8680412, 12607113, 17011332, 22796693). This variant is also known as 441X. ClinVar contains an entry for this variant (Variation ID: 2993). For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780732 | SCV000918242 | pathogenic | not specified | 2018-02-19 | criteria provided, single submitter | clinical testing | Variant summary: SMPD1 c.1327C>T (p.Arg443X) 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. A truncation downstream of this position has been classified as pathogenic by our laboratory (c.1420_1421delCT (p.Leu474fsX20)). The variant allele was found at a frequency of 1.6e-05 in 243788 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (1.6e-05 vs 2.20e-03), allowing no conclusion about variant significance. The variant, c.1327C>T, has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (Wasserstein_2006, Lee_SMPD1_2011, Mukherjee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (Lee_2013). Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) classify the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000193674 | SCV001163307 | pathogenic | Niemann-Pick disease, type A | 2024-03-22 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV001248934 | SCV001422711 | pathogenic | Sphingomyelin/cholesterol lipidosis | 2020-01-22 | criteria provided, single submitter | curation | The p.Arg443Ter variant in SMPD1 (also known as p.Arg441Ter due to a difference in cDNA numbering) has been reported in at least 9 individuals with Niemann-Pick disease (PMID: 22796693, 23415435, 8680412, 17011332, 19405096) and has been identified in 0.004% (4/111364) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074127). 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: 2993) as pathogenic by the University of Chicago, GeneDx, Counsyl, Invitae, Integrated Genetics, and OMIM. This nonsense variant leads to a premature termination codon at position 443, which is predicted to lead to a truncated or absent protein. Although this variant causes loss of function, it is pathogenic without the use of PVS1 and was used to establish whether loss of function is a mechanism of disease. The presence of this variant in 1 affected homozygote and in combination with reported pathogenic or likely pathogenic variants in at least 5 individuals with Niemann-Pick disease increases the likelihood that the p.Arg443Ter variant is pathogenic (VariationID: 93315, 93318, 198093; PMID: 19405096, 22796693, 23415435, 8680412, 17011332). The phenotype of individuals compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 19405096, 22796693, 12607113, 23415435). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the presence of the variant in homozygotes and in trans with other pathogenic variants in affected individuals, the phenotype of patients with the variant being highly specific for disease, and the low frequency in the general population. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP4 (Richards 2015). |
| MGZ Medical Genetics Center | RCV000193674 | SCV002581300 | pathogenic | Niemann-Pick disease, type A | 2022-02-08 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000634567 | SCV002803793 | pathogenic | Niemann-Pick disease, type B; Niemann-Pick disease, type A | 2022-01-14 | criteria provided, single submitter | clinical testing | |
| Neuberg Centre For Genomic Medicine, |
RCV000003127 | SCV004047822 | pathogenic | Niemann-Pick disease, type B | criteria provided, single submitter | clinical testing | The stop gained variant c.1327C>T (p.Arg443Ter) in SMPD1 gene has been reported in individuals affected with Niemann-Pick disease type A and B (Mukherjee SB et.al.,2012). This variant has been reported to the ClinVar database as Pathogenic. The c.1327C>T variant is reported with allele frequency 0.002% in gnomAD exomes and novel in 1000 Genomes. This variant is predicted to cause loss of normal protein function (Ricci V et.al.,2004). Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic . | |
| OMIM | RCV000003127 | SCV000023285 | pathogenic | Niemann-Pick disease, type B | 2003-05-01 | no assertion criteria provided | literature only | |
| Natera, |
RCV000193674 | SCV002092269 | pathogenic | Niemann-Pick disease, type A | 2017-03-17 | no assertion criteria provided | clinical testing |