VCV000499939.13 - ClinVar

NM_000271.5(NPC1):c.1210C>T (p.Arg404Trp)

Germline

Classification

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.

(5)

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

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.1210C>T (p.Arg404Trp)

Variation ID: 499939 Accession: VCV000499939.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q11.2 18: 23556359 (GRCh38) [ NCBI UCSC ] 18: 21136323 (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 2, 2018	Feb 14, 2024	Aug 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000271.5:c.1210C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000262.2:p.Arg404Trp	missense
NC_000018.10:g.23556359G>A
NC_000018.9:g.21136323G>A
NG_012795.1:g.35259C>T

Protein change

R404W

Other names

Canonical SPDI

NC_000018.10:23556358:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA401777639 dbSNP: rs1298238512 VarSome

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
Gene	OMIM	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.
Niemann-Pick disease, type C1	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 17, 2023	RCV000593107.12
not provided	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 21, 2022	RCV000727099.5

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.
Likely pathogenic (Jan 17, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000705676.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	Publications: PubMed (1) PubMed: 12955717 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1 Number of individuals with the variant: 1 Sex: mixed
Likely pathogenic (Sep 21, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003842920.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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: 26659599, 26986070, 12955717, 26981555, 34113546, 33021976, 30942586, 22065762) (less)
Likely pathogenic (Jun 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003815131.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Aug 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000770847.6 First in ClinVar: Apr 02, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 12955717‚ 26981555‚ 11349231‚ 11545687‚ 22065762‚ 26666848‚ 27581084 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 404 of the NPC1 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 404 of the NPC1 protein (p.Arg404Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick type C disease (PMID: 12955717, 26981555). ClinVar contains an entry for this variant (Variation ID: 499939). 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. This variant disrupts the p.Arg404 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11349231, 11545687, 22065762, 26666848, 27581084). 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)
Uncertain significance (Jan 02, 2018)	no assertion criteria provided Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000796805.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 23, 2019	Publications: PubMed (3) PubMed: 26981555‚ 27238017‚ 12955717

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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: 26659599, 26986070, 12955717, 26981555, 34113546, 33021976, 30942586, 22065762)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 404 of the NPC1 protein (p.Arg404Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick type C disease (PMID: 12955717, 26981555). ClinVar contains an entry for this variant (Variation ID: 499939). 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. This variant disrupts the p.Arg404 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11349231, 11545687, 22065762, 26666848, 27581084). 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.	Koens LH	Orphanet journal of rare diseases	2016	PMID: 27581084
Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection.	Gong X	Cell	2016	PMID: 27238017
Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening.	Reunert J	EBioMedicine	2015	PMID: 26981555
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
Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding.	Deffieu MS	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 22065762
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
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 C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.	Sun X	American journal of human genetics	2001	PMID: 11349231
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1	-	-	-	-

Text-mined citations for rs1298238512 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000271.5(NPC1):c.1210C>T (p.Arg404Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1298238512 ...