Submissions for variant NM_000271.5(NPC1):c.1553G>A (p.Arg518Gln)

dbSNP: rs483352886

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000119327	SCV000220893	likely pathogenic	Niemann-Pick disease, type C1	2014-11-17	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000725736	SCV000339053	pathogenic	not provided	2016-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804847	SCV002051425	pathogenic	Niemann-Pick disease, type C	2021-12-30	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.1553G>A (p.Arg518Gln) 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. Experimental studies have shown the variant to result in abberant splicing resulting in a premature termination (Yamamoto_1999). The variant allele was found at a frequency of 4e-06 in 250980 control chromosomes. c.1553G>A has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (Yamamoto_1999, Dardis_2020, Mahmoud_2019, etc). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119327	SCV002234844	pathogenic	Niemann-Pick disease, type C1	2023-05-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in exon 9 and introduces a premature termination codon (PMID: 10480349). The resulting mRNA is expected to undergo nonsense-mediated decay. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 132890). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 10480349, 24001525). This variant is present in population databases (rs483352886, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the NPC1 protein (p.Arg518Gln). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
GeneDx	RCV000725736	SCV002526158	likely pathogenic	not provided	2021-12-09	criteria provided, single submitter	clinical testing	Observed with a second NPC1 variant in unrelated patients with Niemann-Pick disease type C in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some of these cases (Imrie et al., 2015; Costanza et al., 2020); Published functional studies suggest R518Q leads to incomplete alternative splicing resulting in loss of function transcript (Yamamoto et al., 1999); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26666848, 10480349, 24001525, 32138288, 32482919)
Neuberg Centre For Genomic Medicine, NCGM	RCV000119327	SCV004047802	pathogenic	Niemann-Pick disease, type C1		criteria provided, single submitter	clinical testing	The c.1553G>A (p.Arg518Gln) variant in NPC1 gene has been reported in multiple individuals affected with Niemann-Pick Disease Type C (Dardis et al., 2020; Mahmoud et al., 2019). Experimental studies have shown the variant to result in aberrant splicing resulting in a premature termination (Yamamoto et al.,1999). This variant is reported with the allele frequency (0.0003%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/Likely Pathogenic. The amino acid Arg at position 518 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg518Gln in NPC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000119327	SCV000023253	pathogenic	Niemann-Pick disease, type C1	1999-07-01	no assertion criteria provided	literature only
Shanghain Institute for Pediatric Research	RCV000119327	SCV000154186	pathogenic	Niemann-Pick disease, type C1		no assertion criteria provided	not provided	Converted during submission to Pathogenic.