Submissions for variant NM_000271.5(NPC1):c.1351G>A (p.Glu451Lys)

gnomAD frequency: 0.00002  dbSNP: rs781065429

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670724	SCV000795617	uncertain significance	Niemann-Pick disease, type C1	2017-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000670724	SCV000915803	uncertain significance	Niemann-Pick disease, type C1	2017-09-11	criteria provided, single submitter	clinical testing	The NPC1 c.1351G>A (p.Glu451Lys) variant has been reported in a compound heterozygous state with the same second missense variant in seven individuals from two families, a pair of siblings in one family and five siblings in the second family (Tarugi et al. 2002; Romanello et al. 2016). While all individuals were noted to have Niemann-Pick disease (NPCD), four siblings were 'not classified' due to absence of neurological symptoms (Romanello et al. 2016). In addition, the five siblings exhibited a variant biochemical phenotype based on filipin staining and specific types of oxysterols were observed at either below or slightly above the cut-off noted in patients with NPCD (Romanello et al. 2016). The p.Glu451Lys variant was also identified in a heterozygous state in one individual with the early infantile form who also displayed the variant biochemical phenotype; however, in this individual, a second variant was not identified (De Castro-Oros et al. 2017). The p.Glu451Lys variant was absent from 300 control alleles and is reported at a frequency of 0.000305 in the South Asian population of the Exome Aggregation Consortium. Functional studies of the variant have not been conducted, but it results in a nonconservative substitution of a highly conserved amino acid (Tarugi et al. 2002). Based on the collective evidence, the p.Glu451Lys variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000670724	SCV001390377	pathogenic	Niemann-Pick disease, type C1	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 451 of the NPC1 protein (p.Glu451Lys). This variant is present in population databases (rs781065429, gnomAD 0.03%). This missense change has been observed in individual(s) with Niemann-Pick, Type C (PMID: 26790753). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554990). 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.
Baylor Genetics	RCV000670724	SCV001524611	uncertain significance	Niemann-Pick disease, type C1	2019-01-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282310	SCV002572259	likely pathogenic	Niemann-Pick disease, type C	2022-08-23	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1351G>A (p.Glu451Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251370 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4e-05 vs 0.0027), allowing no conclusion about variant significance. c.1351G>A has been reported in the literature in multiple heterozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type C, and has been found to segregate with disease in at least one family (e.g. Tarugi_2022, Romanello_2016, Marques_2016, DeCastro_2017, Benussi_2019). These data indicate that the variant is likely to be associated with disease. It should be noted that Niemann-Pick Disease Type C has a broad clinical presentation and in the literature individuals with the variant predominately present with the variable biochemical phenotype and few neurological symptoms, which can make a definitive diagnosis and variant classification difficult. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (VUS n=4, pathogenic n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000675577	SCV000801268	uncertain significance	not provided	2017-12-01	no assertion criteria provided	clinical testing