Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251462 control chromosomes, predominantly at a frequency of 0.0099 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3343G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C without strong evidence of causality (Rodriguez_2015, Kubaski_2022). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25989649, 35892469). ClinVar contains an entry for this variant (Variation ID: 92712). Based on the evidence outlined above, the variant was classified as likely benign.
ClinVar Genomic variation as it relates to human health
NM_000271.5(NPC1):c.3343G>T (p.Val1115Phe)
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.
(11)
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.
Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(3); Likely benign(2)
Uncertain significance(3); Benign(3); Likely benign(2)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000271.5(NPC1):c.3343G>T (p.Val1115Phe)
Variation ID: 92712 Accession: VCV000092712.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q11.2 18: 23535603 (GRCh38) [ NCBI UCSC ] 18: 21115567 (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 Jun 28, 2015 Oct 20, 2024 Aug 6, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000271.5:c.3343G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000262.2:p.Val1115Phe missense NC_000018.10:g.23535603C>A NC_000018.9:g.21115567C>A NG_012795.1:g.56015G>T - Protein change
- V1115F
- Other names
- -
- Canonical SPDI
- NC_000018.10:23535602: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.
-
0.00300 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00257
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00261
The Genome Aggregation Database (gnomAD) 0.00268
1000 Genomes Project 0.00300
1000 Genomes Project 30x 0.00344
- 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 |
2471 | 2529 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 9, 2024 | RCV000078481.17 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Jan 30, 2024 | RCV000674624.25 | |
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Aug 6, 2024 | RCV000767035.26 | |
|
NPC1-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Apr 10, 2021 | RCV003935016.2 |
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. |
|
|---|---|---|---|---|---|
|
Benign
(Feb 22, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110337.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 28, 2015 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Uncertain significance
(Mar 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816043.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Benign
(Jan 30, 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: SCV001005724.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Feb 09, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004813540.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251462 control chromosomes, predominantly at a frequency of 0.0099 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3343G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C without strong evidence of causality (Rodriguez_2015, Kubaski_2022). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25989649, 35892469). ClinVar contains an entry for this variant (Variation ID: 92712). Based on the evidence outlined above, the variant was classified as likely benign. (less)
|
|
|
Uncertain significance
(May 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease, type C1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000799993.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Benign
(Oct 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Niemann-Pick disease type C1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001283366.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
|
|
|
Uncertain significance
(Aug 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000492076.3
First in ClinVar: Jun 28, 2015 Last updated: Sep 29, 2024 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25764212, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25764212, 25989649, 35892469) (less)
|
|
|
Likely benign
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004140856.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
NPC1: BP4
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807285.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
|
|
|
Likely benign
(Apr 10, 2021)
|
no assertion criteria provided
Method: clinical testing
|
NPC1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004755183.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001964769.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
|
|
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Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25764212, 25989649, 35892469)
Comment:
NPC1: BP4
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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:
Variant summary: NPC1 c.3343G>T (p.Val1115Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251462 control chromosomes, predominantly at a frequency of 0.0099 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.3343G>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C without strong evidence of causality (Rodriguez_2015, Kubaski_2022). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25989649, 35892469). ClinVar contains an entry for this variant (Variation ID: 92712). Based on the evidence outlined above, the variant was classified as likely benign.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25764212, 25989649, 35892469)
Comment:
NPC1: BP4
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Experience of the NPC Brazil Network with a Comprehensive Program for the Screening and Diagnosis of Niemann-Pick Disease Type C. | Kubaski F | International journal of neonatal screening | 2022 | PMID: 35892469 |
| Neurogenetics in Argentina: diagnostic yield in a personalized research based clinic. | Rodríguez-Quiroga SA | Genetics research | 2015 | PMID: 25989649 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1 | - | - | - | - |
Text-mined citations for rs34226296 ...
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 10, 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.