Submissions for variant NM_000271.5(NPC1):c.2842G>A (p.Asp948Asn)

dbSNP: rs1261939149

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668346	SCV000792928	likely pathogenic	Niemann-Pick disease, type C1	2017-07-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000668346	SCV001140858	pathogenic	Niemann-Pick disease, type C1	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668346	SCV001200435	pathogenic	Niemann-Pick disease, type C1	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 948 of the NPC1 protein (p.Asp948Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 10521290, 11349231, 12408188, 23653225). 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: 552987). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479193	SCV004222658	pathogenic	Niemann-Pick disease, type C	2023-11-15	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.2842G>A (p.Asp948Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250712 control chromosomes (gnomAD). c.2842G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C who were reported as compound heterozygous with other pathogenic/likely pathogenic variants (e.g. Greer_1999, Sun_2001, Kaminski_2002, Abela_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 10521290, 12408188, 11349231, 25425405). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.