ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2621A>T (p.Asp874Val) (rs372030650)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724467 SCV000226730 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000175270 SCV000596045 likely pathogenic Niemann-Pick disease type C1 2016-09-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000606384 SCV000712234 pathogenic Niemann-Pick disease, type C 2016-06-20 criteria provided, single submitter clinical testing The p.Asp874Val variant in NPC1 has been reported in at least 6 compound heteroz ygous and 1 homozygous individuals with classic Niemann-Pick disease C (Millat 2 001, Sun 2001, Kaminski 2002, Bauer 2013, Dardis 2016). This variant has also be en identified in 4/120,928 of chromosomes by the Exome Aggregation Consortium (E xAC,; dbSNP rs372030650). Although this variant h as been seen in the general population, its frequency is low enough to be consis tent with a recessive carrier frequency. In summary, the p.Asp874Val variant mee ts our criteria to be classified as pathogenic based on occurrence in trans with pathogenic variants in patients and low frequency in controls.
Fulgent Genetics,Fulgent Genetics RCV000175270 SCV000893488 pathogenic Niemann-Pick disease type C1 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000175270 SCV000915799 pathogenic Niemann-Pick disease type C1 2018-08-22 criteria provided, single submitter clinical testing The NPC1 c.2621A>T (p.Asp874Val) variant has been identified in seven studies in individuals with Niemann-Pick disease, including in a homozygous state in one proband, in a compound heterozygous state in 12 probands, in four additional proband alleles, and in one unaffected heterozygous individual (Sun et al. 2001; Bauer et al. 2002; Kaminski et al. 2002; Park et al. 2003; Bauer et al. 2013; Imrie et al. 2015; Davies-Thompson et al. 2016). The p.Asp874Val variant was absent from 341 controls and is reported at a frequency of 0.000111 in the European (non-Finnish) population of the Genome Aggregation Database. Dardis et al. (2016) demonstrated TAR DNA binding protein 43 localized to the cytoplasm in Purkinje cells versus localization in both cytoplasm and nucleus in Purkinje cells from a healthy individual. Based on the evidence, the p.Asp874Val variant is classified as pathogenic for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000175270 SCV000955560 pathogenic Niemann-Pick disease type C1 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 874 of the NPC1 protein (p.Asp874Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs372030650, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another NPC1 variant in individuals affected with Niemann-Pick Type C (PMID: 11333381, 23773996, 26666848, 17160617, 12408188, 11349231, 11754101). ClinVar contains an entry for this variant (Variation ID: 194810). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000175270 SCV001163438 pathogenic Niemann-Pick disease type C1 criteria provided, single submitter clinical testing
Counsyl RCV000175270 SCV000678169 likely pathogenic Niemann-Pick disease type C1 2014-01-02 no assertion criteria provided clinical testing

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