Submissions for variant NM_000271.5(NPC1):c.3731T>C (p.Leu1244Pro)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003501729	SCV004296911	likely pathogenic	Niemann-Pick disease, type C1	2023-04-26	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 1244 of the NPC1 protein (p.Leu1244Pro). 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. Experimental studies have shown that this missense change affects NPC1 function (PMID: 30923329). 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. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 23433426, 32138288). This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526997	SCV005040228	likely pathogenic	Niemann-Pick disease, type C	2024-03-15	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3731T>C (p.Leu1244Pro) 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 251432 control chromosomes. c.3731T>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (di_Fruscio_2015, Stampfer_2013, Fancello_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26075876, 19252935, 23433426). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.