A heterozygous missense variant in exon 20 of the NPC1 gene that results in the amino acid substitution of Tryptophan for GLycine at codon 992 was detected. The observed variant c.2974G>T (p.Gly992Trp) has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD databases. The in-silico prediction of the variant are possibly damaging by MutationTaster2, DANN and FATHMM. The variant has been previously reported in patient with NPC1 (PMID: 31506030). In summary, the variant meets our criteria to be classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp)
Germline
Classification
Help
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.
(12)
Help
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/Likely pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000271.5(NPC1):c.2974G>T (p.Gly992Trp)
Variation ID: 2960 Accession: VCV000002960.24
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q11.2 18: 23538609 (GRCh38) [ NCBI UCSC ] 18: 21118573 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Sep 1, 2024 Aug 23, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000271.5:c.2974G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Gly992Trp missense NC_000018.10:g.23538609C>A NC_000018.9:g.21118573C>A NG_012795.1:g.53009G>T O15118:p.Gly992Trp - Protein change
- G992W
- Other names
- -
- Canonical SPDI
- NC_000018.10:23538608:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| NPC1 | - | - |
GRCh38 GRCh37 |
2473 | 2531 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 1998 | RCV000003094.3 | |
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Aug 23, 2024 | RCV000020230.21 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Oct 10, 2022 | RCV000723413.11 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Baylor Genetics
Accession: SCV001163436.1
First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020 |
|
|
|
Likely pathogenic
(Mar 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003815154.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV005200104.1
First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024 |
Comment:
A heterozygous missense variant in exon 20 of the NPC1 gene that results in the amino acid substitution of Tryptophan for GLycine at codon 992 … (more)
A heterozygous missense variant in exon 20 of the NPC1 gene that results in the amino acid substitution of Tryptophan for GLycine at codon 992 was detected. The observed variant c.2974G>T (p.Gly992Trp) has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD databases. The in-silico prediction of the variant are possibly damaging by MutationTaster2, DANN and FATHMM. The variant has been previously reported in patient with NPC1 (PMID: 31506030). In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Global developmental delay (present) , Hepatosplenomegaly (present) , Short stature (present) , Failure to thrive (present)
Zygosity: Compound Heterozygote
Age: 0-9 years
Sex: female
Method: DNA extracted from blood was used to perform targeted gene capture using a custom smMIP panel. The libraries were sequenced to mean >100-300X coverage on the Illumina MiSeq sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37) using the BWA program and analyzed using Picard and GATK version 4.1.2 to identify variants relevant to the clinical indication.
|
|
|
Pathogenic
(Aug 07, 2014)
|
criteria provided, single submitter
Method: literature only
|
Niemann-Pick disease type C1
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220581.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Oct 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001781732.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12955717, 11479732, 16778374, 12401890, 10521290, 11545687, 20718790, 9634529, 16126423, 24001525, 26666848, 29961769, 9245994, 31497485, 32222928, 20301473, 32138288, 34535129) (less)
|
|
|
Pathogenic
(Jan 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000941919.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 992 of the NPC1 protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 992 of the NPC1 protein (p.Gly992Trp). This variant is present in population databases (rs80358254, gnomAD 0.003%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 9634529, 11545687, 16778374, 20718790, 26666848, 28222799). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11333381, 16126423, 26984608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Niemann-Pick disease type C1
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453837.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Likely pathogenic
(Jun 02, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Niemann-Pick disease, type C1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
|
Hereditary Research Laboratory, Bethlehem University
Accession: SCV001653519.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Zygosity: Homozygote
Ethnicity/Population group: Palestinian
Geographic origin: Palestine
|
|
|
Pathogenic
(Jul 01, 1998)
|
no assertion criteria provided
Method: literature only
|
NIEMANN-PICK DISEASE, TYPE D
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023252.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2024 |
Comment on evidence:
Greer et al. (1997) mapped the Nova Scotian type of Niemann-Pick disease, also called type D (see 257220), to a 13-cM chromosome segment between D18S40 … (more)
Greer et al. (1997) mapped the Nova Scotian type of Niemann-Pick disease, also called type D (see 257220), to a 13-cM chromosome segment between D18S40 and D18S66. A gene isolated from this region, NPC1, had been found to be mutated in most patients with Niemann-Pick disease type C. Greer et al. (1998) identified a point mutation within the NPC1 gene (3097G-T, G992W) that showed complete linkage disequilibrium with the Nova Scotian form, confirming that type D is an allelic variant of NPC1. (less)
|
|
|
Likely pathogenic
(Jun 07, 2017)
|
no assertion criteria provided
Method: curation
|
Niemann-Pick disease, type C1
Affected status: no
Allele origin:
germline
|
SingHealth Duke-NUS Institute of Precision Medicine
Accession: SCV000853138.1
First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Niemann-Pick disease, type C1
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000040574.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
|
Uncertain significance
(Oct 25, 2016)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000700313.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Zygosity: Single Heterozygote
Sex: mixed
|
|
| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12955717, 11479732, 16778374, 12401890, 10521290, 11545687, 20718790, 9634529, 16126423, 24001525, 26666848, 29961769, 9245994, 31497485, 32222928, 20301473, 32138288, 34535129)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 992 of the NPC1 protein (p.Gly992Trp). This variant is present in population databases (rs80358254, gnomAD 0.003%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 9634529, 11545687, 16778374, 20718790, 26666848, 28222799). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11333381, 16126423, 26984608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
A heterozygous missense variant in exon 20 of the NPC1 gene that results in the amino acid substitution of Tryptophan for GLycine at codon 992 was detected. The observed variant c.2974G>T (p.Gly992Trp) has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD databases. The in-silico prediction of the variant are possibly damaging by MutationTaster2, DANN and FATHMM. The variant has been previously reported in patient with NPC1 (PMID: 31506030). In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12955717, 11479732, 16778374, 12401890, 10521290, 11545687, 20718790, 9634529, 16126423, 24001525, 26666848, 29961769, 9245994, 31497485, 32222928, 20301473, 32138288, 34535129)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 992 of the NPC1 protein (p.Gly992Trp). This variant is present in population databases (rs80358254, gnomAD 0.003%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 9634529, 11545687, 16778374, 20718790, 26666848, 28222799). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly992 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11333381, 16126423, 26984608). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Niemann-Pick Disease Type C. | Adam MP | - | 2020 | PMID: 20301473 |
| Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study. | De Castro-Orós I | Journal of translational medicine | 2017 | PMID: 28222799 |
| Normalisation of brain spectroscopy findings in Niemann-Pick disease type C patients treated with miglustat. | Sedel F | Journal of neurology | 2016 | PMID: 26984608 |
| 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 |
| Molecular analysis of 30 Niemann-Pick type C patients from Spain. | Macías-Vidal J | Clinical genetics | 2011 | PMID: 20718790 |
| Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid. | Oyama K | The Tohoku journal of experimental medicine | 2006 | PMID: 16778374 |
| 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 |
| 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 |
| Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C. | Meiner V | Genetics in medicine : official journal of the American College of Medical Genetics | 2001 | PMID: 11545687 |
| Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. | Millat G | American journal of human genetics | 2001 | PMID: 11333381 |
| The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1. | Greer WL | American journal of human genetics | 1998 | PMID: 9634529 |
| Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C. | Greer WL | American journal of human genetics | 1997 | PMID: 9245994 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs80358254 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 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.