Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000729578 | SCV000857251 | uncertain significance | not provided | 2018-03-23 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001416117 | SCV001618289 | likely benign | Niemann-Pick disease, type C1 | 2025-01-27 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV001416117 | SCV003816037 | uncertain significance | Niemann-Pick disease, type C1 | 2022-03-08 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004586579 | SCV005076209 | uncertain significance | not specified | 2024-04-29 | criteria provided, single submitter | clinical testing | Variant summary: NPC1 c.1937G>A (p.Arg646His) results in a non-conservative amino acid change located in the Sterol-sensing domain (IPR000731) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250692 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (6.4e-05 vs 0.0027), allowing no conclusion about variant significance. c.1937G>A has been reported in the literature in a study including patients with lysosomal storage disorders (Malaga_2019), however it was found in cis with two other missense variants and patient information was not provided. This report does not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30985853). ClinVar contains an entry for this variant (Variation ID: 181451). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Prevention |
RCV003407591 | SCV004107628 | uncertain significance | NPC1-related disorder | 2024-08-14 | no assertion criteria provided | clinical testing | The NPC1 c.1937G>A variant is predicted to result in the amino acid substitution p.Arg646His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.081% of alleles in individuals of African descent in gnomAD, which is likely too frequent to be a primary cause of disease. Although we suspect this variant may be benign, its clinical significance is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. |