ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2974G>C (p.Gly992Arg) (rs80358254)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003103 SCV000220328 likely pathogenic Niemann-Pick disease type C1 2014-05-19 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000489250 SCV000331815 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing
GeneDx RCV000489250 SCV000576990 pathogenic not provided 2017-04-13 criteria provided, single submitter clinical testing The G992R missense variant in the NPC1 gene has been reported previously in the homozygous state in an adultwith a variant biochemical phenotype and no reported neurological symptoms (Millat et al., 2001). The G992Rvariant has also been reported previously in individuals with classic Niemann-Pick disease type C (NPC) who werealso found to harbor another NPC1 gene variant (Millat et al., 2005; Piña-Aguilar et al., 2014; Romanello et al.,2016 ). The G992R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016;1000 Genomes Consortium et al., 2015; Exome Variant Server). The G992R variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. This substitution occurs at a position that is conserved across species. In silico analysispredicts this variant is probably damaging to the protein structure/function. Many variants in the NPC1 gene areconcentrated within the cysteine-rich luminal loop and are specifically clustered in a hot spot region around aminoacid 992 (Millat et al., 2005). In summary, we interpret G992R as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000590044 SCV000696418 pathogenic Niemann-Pick disease, type C 2017-04-26 criteria provided, single submitter clinical testing Variant summary: The NPC1 c.2974G>C (p.Gly992Arg) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121558 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). This variant has been reported in NPC patients (mostly adult-onset) both as homozygote and compound heterozygote. Another variant involving the same nucleotide G2974A, causing the same amino acid change G992R, has also been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000003103 SCV000934524 pathogenic Niemann-Pick disease type C1 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 992 of the NPC1 protein (p.Gly992Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs80358254, ExAC 0.01%). This variant has been observed as homozygous or in combination with another NPC1 variant in several individuals affected with Niemann-Pick disease type C (PMID: 11333381, 16126423, 26984608). ClinVar contains an entry for this variant (Variation ID: 2969). 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.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 9634529, 12955717, 16126423, 20718790), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000489250 SCV001371367 likely pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
OMIM RCV000003103 SCV000023261 pathogenic Niemann-Pick disease type C1 2004-12-14 no assertion criteria provided literature only
GeneReviews RCV000003103 SCV000040573 pathologic Niemann-Pick disease type C1 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.

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