ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs) (rs756815030)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169300 SCV000220619 likely pathogenic Niemann-Pick disease type C1 2014-08-21 criteria provided, single submitter literature only
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415902 SCV000493648 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Invitae RCV000169300 SCV000824255 pathogenic Niemann-Pick disease type C1 2020-10-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln991Argfs*15) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs756815030, ExAC 0.009%). This variant has been observed to be homozygous or in combination with another NPC1 variant in several individuals affected with Niemann-Pick disease type C (PMID: 12401890, 16126423, 23427322, 24915861, 26666848). This variant is also known as 2972del2 in the literature. ClinVar contains an entry for this variant (Variation ID: 188932). Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169300 SCV000915796 pathogenic Niemann-Pick disease type C1 2018-06-19 criteria provided, single submitter clinical testing The NPC1 c.2972_2973delAG (p.Gln991ArgfsTer15) variant has been reported in at least seven studies and is found in at least seven patients with suspected Neimann-Pick disease type C, including one in a homozygous state, five in a compound heterozygous state, and two in a heterozygous state where a second variant was not identified (Greer et al. 1999; Tarugi et al. 2002; Park et al. 2003; Fancello et al. 2009; Schicks et al. 2013; Zhang et al. 2014; Imrie et al. 2015). The p.Gln991ArgfsTer15 variant was absent from 250 controls but is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Genome Aggregation Database. Data from Tarugi et al. (2002) suggest the allele carrying p.Gln991ArgfsTer15 is not transcribed or mRNA is rapidly degraded making it non-functional, as the allele was not identified using reverse transcription of RNA in fibroblasts of two unrelated compound heterozygous patients. Based on the evidence and the potential impact of frameshift variants, the p.Gln991ArgfsTer15 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781673 SCV000919897 pathogenic Niemann-Pick disease, type C 2018-07-19 criteria provided, single submitter clinical testing Variant summary: NPC1 c.2972_2973delAG (p.Gln991ArgfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3742_3745delCTCA (p.Leu1248fsX3)). The variant allele was found at a frequency of 4.7e-05 in 277230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4.7e-05 vs 0.0028), allowing no conclusion about variant significance. c.2972_2973delAG has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C, including several homozygous patients who are severely affected (e.g. Millat_2005, Fancello_2009, Elmonem_2016). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000415902 SCV001447874 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000781673 SCV001653013 pathogenic Niemann-Pick disease, type C 2020-06-09 criteria provided, single submitter clinical testing The p.Gln991ArgfsX15 variant in NPC1 has been reported in at least 8 individuals with Neimann-Pick Type C, in the compound heterozygous (5), homozygous (2) or heterozygous state (1) (Greer 1999 PMID: 10521290, Tarugi 2002 PMID: 12401890, Palmeri 2005 PMID: 16086131, Millat 2005 PMID: 16126423, Schicks 2013 PMID: 23427322, Imrie 2015 PMID: 26666848, Elmonem 2016 PMID: 26830282). It has also been identified in 0.01% (2/30616) of South Asian chromosomes by gnomAD ( However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 188932). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 991 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NPC1 gene is an established disease mechanism in autosomal recessive Niemann-Pick Type C Disease. In vitro functional studies provide some evidence that this variant does impacts protein function (Tarugi 2002 PMID: 12401890); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Niemann-Pick Type C Disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PS3_Supporting.
GeneDx RCV000415902 SCV001820391 pathogenic not provided 2021-04-20 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32138288, 26790753, 24915861, 12955717, 12401890, 16086131, 26666848, 10521290, 23427322, 16126423)

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