ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(7); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs)
Variation ID: 188932 Accession: VCV000188932.50
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 18q11.2 18: 23538610-23538611 (GRCh38) [ NCBI UCSC ] 18: 21118574-21118575 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Oct 20, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000271.5:c.2972_2973del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Gln991fs frameshift NM_000271.4:c.2972_2973del NC_000018.10:g.23538610_23538611del NC_000018.9:g.21118574_21118575del NG_012795.1:g.53007_53008del - Protein change
- Q991fs
- Other names
- -
- Canonical SPDI
- NC_000018.10:23538609:CT:
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00005
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NPC1 | - | - |
GRCh38 GRCh37 |
2471 | 2529 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000169300.17 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Dec 13, 2022 | RCV000415902.30 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 9, 2020 | RCV000781673.7 | |
NPC1-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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May 19, 2023 | RCV003416051.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Jul 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919897.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447874.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Urinary incontinence (present) , Torticollis (present) , Cerebellar atrophy (present) , Gait ataxia (present) , Memory impairment (present) , Abnormal pyramidal sign (present) , Abnormality … (more)
Urinary incontinence (present) , Torticollis (present) , Cerebellar atrophy (present) , Gait ataxia (present) , Memory impairment (present) , Abnormal pyramidal sign (present) , Abnormality of the urinary system (present) , Gaze-evoked nystagmus (present) , Dysmetric saccades (present) , Cerebellar ataxia (present) , Spasticity (present) , Babinski sign (present) (less)
Sex: female
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Pathogenic
(Jun 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653013.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001820391.2
First in ClinVar: Sep 08, 2021 Last updated: Dec 24, 2022 |
Comment:
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 … (more)
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) (less)
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Likely pathogenic
(Aug 21, 2014)
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criteria provided, single submitter
Method: literature only
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Niemann-Pick disease type C1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000220619.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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NPC1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004118429.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000824255.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jul 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000493648.33
First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915796.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 22, 2021)
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no assertion criteria provided
Method: clinical testing
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Niemann-Pick disease type C1
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002095175.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Lysosomal Storage Disorders in Egyptian Children. | Elmonem MA | Indian journal of pediatrics | 2016 | PMID: 26830282 |
Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database. | Imrie J | BMC neurology | 2015 | PMID: 26666848 |
Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. | Zhang H | Orphanet journal of rare diseases | 2014 | PMID: 24915861 |
Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy. | Schicks J | Neurology | 2013 | PMID: 23427322 |
Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations. | Fancello T | Neurogenetics | 2009 | PMID: 19252935 |
Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. | Millat G | Molecular genetics and metabolism | 2005 | PMID: 16126423 |
Lung involvement in Niemann-Pick disease type C1: improvement with bronchoalveolar lavage. | Palmeri S | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2005 | PMID: 16086131 |
Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. | Park WD | Human mutation | 2003 | PMID: 12955717 |
Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts. | Tarugi P | Journal of lipid research | 2002 | PMID: 12401890 |
Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. | Greer WL | American journal of human genetics | 1999 | PMID: 10521290 |
Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. | Loftus SK | Science (New York, N.Y.) | 1997 | PMID: 9211850 |
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Text-mined citations for rs756815030 ...
HelpRecord last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.