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

gnomAD frequency: 0.00001  dbSNP: rs756815030

Total submissions: 10

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 Center for Human Genetics 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	2024-01-25	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. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). This variant is present in population databases (rs756815030, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Niemann-Pick disease type C (PMID: 12401890, 16126423, 23427322, 24915861, 26666848). This variant is also known as 2972del2. ClinVar contains an entry for this variant (Variation ID: 188932). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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, Mass General Brigham 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 (http://gnomad.broadinstitute.org). 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	2022-12-13	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 (gnomAD); This variant is associated with the following publications: (PMID: 23427322, 16126423, 12955717, 10521290, 26666848, 16086131, 12401890, 24915861, 26790753, 32138288)
PreventionGenetics, part of Exact Sciences	RCV003416051	SCV004118429	pathogenic	NPC1-related condition	2023-05-19	criteria provided, single submitter	clinical testing	The NPC1 c.2972_2973delAG variant is predicted to result in a frameshift and premature protein termination (p.Gln991Argfs*15). This variant has been reported in individuals with Niemann-Pick type C (Tarugi et al. 2002. PubMed ID: 12401890; Millat et al. 2005. PubMed ID: 16126423; Schicks et al. 2013. PubMed ID: 23427322; Zhang et al. 2014. PubMed ID: 24915861; Imrie et al. 2015. PubMed ID: 26666848). This variant is reported in 0.0096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21118573-CCT-C). Frameshift variants in NPC1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Natera, Inc.	RCV000169300	SCV002095175	pathogenic	Niemann-Pick disease, type C1	2021-06-22	no assertion criteria provided	clinical testing