ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3560C>T (p.Ala1187Val)

gnomAD frequency: 0.00004  dbSNP: rs113371321
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671937 SCV000796978 uncertain significance Niemann-Pick disease, type C1 2018-01-05 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000729488 SCV000857156 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing
Invitae RCV000671937 SCV001411764 uncertain significance Niemann-Pick disease, type C1 2022-09-07 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1187 of the NPC1 protein (p.Ala1187Val). This variant is present in population databases (rs113371321, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick Type C (PMID: 19252935, 31130284, 32138288). ClinVar contains an entry for this variant (Variation ID: 556002). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Ala1187 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26981555; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV000671937 SCV002792578 uncertain significance Niemann-Pick disease, type C1 2021-09-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV002532118 SCV003693037 uncertain significance Inborn genetic diseases 2022-10-25 criteria provided, single submitter clinical testing The c.3560C>T (p.A1187V) alteration is located in exon 23 (coding exon 23) of the NPC1 gene. This alteration results from a C to T substitution at nucleotide position 3560, causing the alanine (A) at amino acid position 1187 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV000729488 SCV003929761 uncertain significance not provided 2022-11-25 criteria provided, single submitter clinical testing Identified in adults with psychotic symptoms in published literature (Fancello et al., 2009; Sriretnakumar et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 19252935, 32138288, 31130284, 30556376, 34670123)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003403563 SCV004121789 uncertain significance not specified 2023-10-18 criteria provided, single submitter clinical testing Variant summary: NPC1 c.3560C>T (p.Ala1187Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251064 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.00012 vs 0.0027), allowing no conclusion about variant significance. c.3560C>T has been reported in the literature in individuals affected with clinical features of Niemann-Pick Type C (examples: Fancello_2009, Monies_2019, Sriretnakumar_2019, Dardis_2020, Chen_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30556376, 35861376, 32138288, 19252935, 31130284, 33138774). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000671937 SCV002095161 uncertain significance Niemann-Pick disease, type C1 2020-02-08 no assertion criteria provided clinical testing

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