Submissions for variant NM_000271.5(NPC1):c.2108T>C (p.Phe703Ser)

dbSNP: rs2058753693

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001797017	SCV002038537	likely pathogenic	Niemann-Pick disease, type C1	2021-06-25	criteria provided, single submitter	clinical testing	The NPC1 c.2108T>C (p.Phe703Ser) variant is a missense variant that has been reported in one individual, a Japanese female with late infantile onset Niemann-Pick disease, type C, who was also found to carry a stop-gained variant, presumably in trans (Yamamoto et al. 2000; Kodachi et al. 2017). The p.Phe703Ser variant is not found in v2.1.1 or v3.1.1 of the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. The Phe703 residue is located in transmembrane domain 5 which is part of the sterol sensing SSD domain, a region in which other disease-causing missense variants have been previously described (Scott et al. 2004; Landrum et al. 2018; Dubey et al. 2020). In silico prediction tools suggest that the p.Phe703Ser variant confers a damaging effect, however this has not been verified experimentally. Based on the collective evidence, the p.Phe703Ser variant is classified as likely pathogenic for Niemann-Pick disease, type C.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001797017	SCV002288917	likely pathogenic	Niemann-Pick disease, type C1	2022-10-18	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Phe703 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 32921771), which suggests that this may be a clinically significant amino acid residue. Studies have shown that this missense change alters NPC1 gene expression (PMID: 11182931). 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: 1328533). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 28387450). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 703 of the NPC1 protein (p.Phe703Ser).