Submissions for variant NM_000271.5(NPC1):c.3572T>C (p.Leu1191Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003606671	SCV004509792	likely pathogenic	Niemann-Pick disease, type C1	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1191 of the NPC1 protein (p.Leu1191Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. 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 with a positive predictive value of 95%. This variant disrupts the p.Leu1191 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19252935, 23430855). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701802	SCV005203696	uncertain significance	not specified	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3572T>C (p.Leu1191Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250876 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3572T>C in individuals affected with Niemann-Pick Disease Type C and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2885670). Based on the evidence outlined above, the variant was classified as uncertain significance.