ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000020229 SCV000220329 likely pathogenic Niemann-Pick disease type C1 2014-05-19 criteria provided, single submitter literature only
GeneDx RCV000413372 SCV000491260 pathogenic not provided 2016-10-21 criteria provided, single submitter clinical testing The G992R pathogenic variant in the NPC1 gene, resulting from either c.2974G>A or c.2974G>C, has been reported previously in multiple individuals with Niemann-Pick disease type C (Millat et al., 2001; Walterfang et al., 2009; Piña-Aguilar et al., 2014; Sedel et al., 2016; Romanello et al., 2016). The G992R variant was not observed in approximately 6,500 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 G992R 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts it is probably damaging to the protein structure/function. A different variant at the same residue (R992W) has also been reported in multiple individuals with Niemann-Pick disease type C (Greer et al., 1998; Greer et al., 1999), supporting the functional importance of this residue. We interpret G992R as a pathogenic variant.
GeneReviews RCV000020229 SCV000040572 pathologic Niemann-Pick disease type C1 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.

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