Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825537 | SCV000966853 | likely pathogenic | Niemann-Pick disease, type C | 2019-02-11 | criteria provided, single submitter | clinical testing | The p.Gln438X variant in NPC1 has not been previously reported in individuals with Niemann-Pick disease type C, but has been identified in 0.003% (1/34590) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 438, which is predicted to lead to a truncated or absent protein. Loss of function of the NPC1 gene is an established disease mechanism in Niemann-Pick disease type C. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Niemann-Pick disease type C. ACMG/AMP Criteria applied: PVS1, PM2. |
| Labcorp Genetics |
RCV001858400 | SCV002144518 | pathogenic | Niemann-Pick disease, type C1 | 2024-10-24 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln438*) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 666979). For these reasons, this variant has been classified as Pathogenic. |