ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2861C>T (p.Ser954Leu) (rs543206298)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254670 SCV000208909 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The S954L missense change is a common pathogenic variant associated with Niemann-Pick disease, type C (NPC) in European individuals (Greer et al.,1999; Stampfer et al., 2013; Jahnova et al., 2014). S954L is believed to result in a milder NPC phenotype as it has been reported in individuals with juvenile and adult-onset NPC who also harbored a null pathogenic NPC1 variant (Jahnova et al., 2014). The S954L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The S954L variant is located within Loop I of the NPC1 protein, where a large number of pathogenic variants have previously been identified, supporting the functional importance of this region of the protein (Scott et al., 2004) The S954L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret S954L to be a pathogenic variant.
Invitae RCV000158972 SCV000770849 pathogenic Niemann-Pick disease type C1 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 954 of the NPC1 protein (p.Ser954Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs543206298, ExAC 0.02%). This variant has been reported in combination with other variants in the NPC1 gene, some of them pathogenic, in several individuals affected with Niemann-Pick disease (PMID: 11182931, 12401890, 23773996, 24915861, 26666848, 27581084). ClinVar contains an entry for this variant (Variation ID: 181457). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000158972 SCV000893486 pathogenic Niemann-Pick disease type C1 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000158972 SCV001149856 pathogenic Niemann-Pick disease type C1 2018-10-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254670 SCV001335074 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193400 SCV001362189 pathogenic Niemann-Pick disease, type C 2019-07-09 criteria provided, single submitter clinical testing Variant summary: NPC1 c.2861C>T (p.Ser954Leu) results in a non-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 7.6e-05 in 251102 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (7.6e-05 vs 0.0028), allowing no conclusion about variant significance. The variant, c.2861C>T, has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (e.g. Reunert_2016, Tarugi_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000158972 SCV000220623 pathogenic Niemann-Pick disease type C1 2019-07-23 no assertion criteria provided clinical testing

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