ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln) (rs139751448)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169124 SCV000220334 likely pathogenic Niemann-Pick disease type C1 2014-05-20 criteria provided, single submitter literature only
GeneDx RCV000255152 SCV000321923 pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing The R404Q pathogenic variant in the NPC1 gene has been reported previously in individuals diagnosed with Niemann-Pick disease type C (Millat et al., 2001; Sun et al., 2001; Meiner et al., 2001). The R404Q variant is relatively common in affected patients, occurring on 3.1% of NPC1 alleles (Park et al., 2003). The R404Q variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R404Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. An in vitro binding study demonstrated that the R404Q variant interferes with the ability of the NPC1 protein to bind NPC2; binding was approximately half of that observed with wild-type protein (Deffieu et al., 2011). We interpret R404Q as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000169124 SCV000596047 pathogenic Niemann-Pick disease type C1 2017-03-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588149 SCV000696414 pathogenic Niemann-Pick disease, type C 2016-12-01 criteria provided, single submitter clinical testing Variant summary: The c.1211G>A (p.Arg404Gln) in NPC1 gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. These predictions were also confirmed by functional studies, where very low esterification values were found in fibroblasts of a patient homozygous for R404Q. The variant is present in the large control population dataset of ExAC at a frequency 0.000041 (5/121346 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant (0.0028). The variant was identified in multiple affected individuals with established dx of classical NPC. Lastly, multiple reputable diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000169124 SCV000893491 pathogenic Niemann-Pick disease type C1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000169124 SCV000956950 pathogenic Niemann-Pick disease type C1 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 404 of the NPC1 protein (p.Arg404Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs139751448, ExAC 0.009%). This variant has been observed in several individuals affected with Nieman-Pick disease type C (PMID: 27581084, 26666848, 11545687, 11349231, Invitae). ClinVar contains an entry for this variant (Variation ID: 188794). Experimental studies have shown that this missense change disrupts the NPC1 protein binding capacity (PMID: 22065762). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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