Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000603315 | SCV000712090 | likely pathogenic | Niemann-Pick disease, type C | 2016-05-10 | criteria provided, single submitter | clinical testing | The p.Thr1205Arg variant in NPC1 has been previously reported in three individua ls with Niemann-Pick disease type C (Yamamoto 2000, Park 2003, Jahnova 2014). At least 2 of these individuals carried the variant in a compound heterozygous sta te (Yamamoto 2000, Jahnova 2014). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that t he p.Thr1205Arg variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Thr1205Arg variant is likely pathogenic. |
| Invitae | RCV000815386 | SCV000955836 | pathogenic | Niemann-Pick disease type C1 | 2018-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with arginine at codon 1205 of the NPC1 protein (p.Thr1205Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Niemann-Pick Type C (PMID: 11182931, 22676771, 25236789). ClinVar contains an entry for this variant (Variation ID: 505018). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Thr1205 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15130691, 22676771, 12955717, 23430855, 11182931, 25236789), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. |