Submissions for variant NM_000271.5(NPC1):c.1301C>T (p.Pro434Leu)

gnomAD frequency: 0.00002  dbSNP: rs774333145

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494559	SCV000581861	likely pathogenic	not provided	2015-08-16	criteria provided, single submitter	clinical testing	The P434L variant has been reported previously in an individual with a biochemical diagnosis of Niemann-Pick disease type C (NPC) who also carried another missense variant in the NPC1 gene, although phase was not determined and functional studies were not performed (Fernandez-Valero et al., 2005). The P434L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (P433L) has been reported in the Human Gene Mutation Database in association with NPC (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the P434L variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Counsyl	RCV000670030	SCV000794841	uncertain significance	Niemann-Pick disease, type C1	2017-10-17	criteria provided, single submitter	clinical testing
Invitae	RCV000670030	SCV003442583	pathogenic	Niemann-Pick disease, type C1	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 434 of the NPC1 protein (p.Pro434Leu). This variant is present in population databases (rs774333145, gnomAD 0.007%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 16098014, 26981555, 36325261). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 429322). 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 not expected to disrupt NPC1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.