Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000176359 | SCV000228000 | uncertain significance | not provided | 2014-08-14 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000704311 | SCV000833255 | pathogenic | Niemann-Pick disease, type C1 | 2023-04-25 | criteria provided, single submitter | clinical testing | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. ClinVar contains an entry for this variant (Variation ID: 195723). This missense change has been observed in individual(s) with Niemann-Pick C (PMID: 11349231, 17160617, 19744920, 23430855, 25349751, 26666848). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1165 of the NPC1 protein (p.Val1165Met). For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV000704311 | SCV002557735 | pathogenic | Niemann-Pick disease, type C1 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Niemann-Pick disease type C1 and type D (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32138288). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated patched domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more recently as likely pathogenic (ClinVar). It has been observed in multiple compound heterozygous and homozygous individuals with late-infantile, juvenile or adult-onset Neimann-Pick disease type C (NPC; PMID: 32138288, PMID: 26666848). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Cells of an individual with NPC, demonstrated significant increases in cholesterol accumulation (PMID: 33163944). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Natera, |
RCV000704311 | SCV001453830 | likely pathogenic | Niemann-Pick disease, type C1 | 2020-09-16 | no assertion criteria provided | clinical testing |