VCV000002967.72 - ClinVar

NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)

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.

(24)

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

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.3182T>C (p.Ile1061Thr)

Variation ID: 2967 Accession: VCV000002967.72

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q11.2 18: 23536736 (GRCh38) [ NCBI UCSC ] 18: 21116700 (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	Nov 24, 2024	Sep 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000271.5:c.3182T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000262.2:p.Ile1061Thr	missense
NC_000018.10:g.23536736A>G
NC_000018.9:g.21116700A>G
NG_012795.1:g.54882T>C
	O15118:p.Ile1061Thr

... more HGVS ... less HGVS

Protein change

I1061T

Other names

p.I1061T:ATA>ACA

Canonical SPDI

NC_000018.10:23536735:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00023

Exome Aggregation Consortium (ExAC) 0.00024

The Genome Aggregation Database (gnomAD) 0.00025

Links

OMIM: 607623.0010 dbSNP: rs80358259 ClinGen: CA340033 UniProtKB: O15118#VAR_008836 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	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.
Niemann-Pick disease, type C1	Pathogenic (14)	criteria provided, multiple submitters, no conflicts	Sep 21, 2024	RCV000003101.42
not provided	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jun 1, 2023	RCV000254672.36
Niemann-Pick disease, type C	Pathogenic (1)	criteria provided, single submitter	Jun 28, 2022	RCV000587869.4
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Sep 7, 2014	RCV000624446.4
Sphingomyelin/cholesterol lipidosis	Pathogenic (1)	criteria provided, single submitter	-	RCV003335012.1
NPC1-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 16, 2024	RCV003964790.2

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.
Pathogenic (Nov 18, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000596044.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (May 05, 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: SCV000330979.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 18216017‚ 23430855 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: 17 Sex: mixed
Pathogenic (Nov 12, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193866.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020	Publications: PubMed (9) PubMed: 12401890‚ 10521290‚ 10480349‚ 21436030‚ 16098014‚ 11349231‚ 11754101‚ 18216017‚ 22505584 Comment: NM_000271.4(NPC1):c.3182T>C(I1061T) is classified as pathogenic in the context of Niemann-Pick disease, type C1. Sources cited for classification include the following: PMID 12401890, 10521290, 10480349, 21436030, … (more) NM_000271.4(NPC1):c.3182T>C(I1061T) is classified as pathogenic in the context of Niemann-Pick disease, type C1. Sources cited for classification include the following: PMID 12401890, 10521290, 10480349, 21436030, 16098014, 11349231, 11754101, 18216017 and 22505584. Classification of NM_000271.4(NPC1):c.3182T>C(I1061T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Mar 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502267.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (30) PubMed: 10480349‚ 14639697‚ 28710748‚ 31589614‚ 32138288‚ 25637190‚ 18216017‚ 31639011‚ 31980526‚ 26666848‚ 20521171‚ 28865947‚ 10521297‚ 24928400‚ 28413817‚ 21436030‚ 26019327‚ 25873482‚ 30487145‚ 29631617‚ 30556376‚ 28776642‚ 29476731‚ 27923633‚ 25149939‚ 33099109‚ 30665703‚ 22505584‚ 23430855‚ 25590979 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jun 28, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Niemann-Pick disease, type C Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696420.2 First in ClinVar: Mar 17, 2018 Last updated: Aug 03, 2022	Publications: PubMed (2) PubMed: 18216017‚ 10521297 Comment: Variant summary: NPC1 c.3182T>C (p.Ile1061Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: NPC1 c.3182T>C (p.Ile1061Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251630 control chromosomes. This variant has been shown to be the most common mutation in NPC patients (Millat_1999). Functional study showed that the protein levels of NPC1 I1061T was significantly lower than the wild-type NPC1 due to misfolding (Gelsthorpe_2008). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 17, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611222.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022
Pathogenic (Apr 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Niemann-Pick disease, type C1 Affected status: yes Allele origin: biparental	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003919012.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Publications: PubMed (1) PubMed: 25590979
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NIEMANN-PICK DISEASE Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046002.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: This variant is one of the most common alterations identified in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 25149939, 20521171, 10480349). Functional characterization … (more) This variant is one of the most common alterations identified in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 25149939, 20521171, 10480349). Functional characterization showed that the variant impairs proper protein localization and leads to proteasomal degradation in cell culture (PMID: 18216017, 25637190). The c.3182T>C (p.Ile1061Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.019% (53/282832) and thus is presumed to be rare. The c.3182T>C (p.Ile1061Thr) variant is predicted by in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3182T>C (p.Ile1061Thr) variant is classified as Pathogenic. (less)
Pathogenic (Jan 11, 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: SCV002018348.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 10, 2015)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: yes Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236543.2 First in ClinVar: Jul 05, 2015 Last updated: Jul 12, 2015
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163434.1 First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020
Pathogenic (Sep 07, 2014)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000742470.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 21436030‚ 18216017 Number of individuals with the variant: 1 Clinical Features: Developmental regression (present) , Intellectual disability (present) , Vertical supranuclear gaze palsy (present) , Muscular hypotonia (present) , Epistaxis (present) , Difficulty walking (present) , … (more) Developmental regression (present) , Intellectual disability (present) , Vertical supranuclear gaze palsy (present) , Muscular hypotonia (present) , Epistaxis (present) , Difficulty walking (present) , Behavioral abnormality (present) , Inappropriate laughter (present) , Drooling (present) , Dysarthria (present) , Gait imbalance (present) , Fatigue (present) , Motor deterioration (present) , Flexion contracture (present) (less) Sex: male Ethnicity/Population group: Hispanic
Pathogenic (Feb 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208911.13 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: In vitro studies of I1061T in human fibroblasts demonstrated that the protein fails to undergo normal glycosylation, leading to misfolding and degradation (Gelsthorpe et al., … (more) In vitro studies of I1061T in human fibroblasts demonstrated that the protein fails to undergo normal glycosylation, leading to misfolding and degradation (Gelsthorpe et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28865947, 31589614, 31980526, 32138288, 31639011, 29476731, 29631617, 28776642, 28413817, 27923633, 25873482, 10480349, 25637190, 26019327, 24928400, 25149939, 10521297, 22505584, 23430855, 21436030, 20521171, 18216017, 25590979, 23521787, 26666848, 14639697, 28710748, 30487145, 30665703, 30556376) (less)
Pathogenic (Jan 24, 2024)	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: SCV000836750.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 28492532‚ 10521297‚ 16126423‚ 20521171‚ 25149939‚ 18216017‚ 25637190‚ 26019327 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1061 of the NPC1 protein (p.Ile1061Thr). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1061 of the NPC1 protein (p.Ile1061Thr). This variant is present in population databases (rs80358259, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 20521171, 25149939). It is commonly reported in individuals of American and Western European ancestry (PMID: 10521297). ClinVar contains an entry for this variant (Variation ID: 2967). 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%. Experimental studies have shown that this missense change affects NPC1 function (PMID: 18216017, 25637190, 26019327). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249522.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: NPC1: PM3:Very Strong, PM2, PS3:Supporting Number of individuals with the variant: 10
Pathogenic (Sep 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086756.2 First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 32138288‚ 35140266 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type C1 Niemann-Pick disease (MIM#257220) and type D Niemann-Pick disease (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been observed amongst individuals carrying the same pathogenic variant (PMID: 32138288). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (53 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid c(SP) 0600 - Variant is located in the annotated Patched family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous or homozygous in many individuals with Niemann-Pick disease type C1 (PMID: 35140266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (May 07, 2015)	no assertion criteria provided Method: research	Niemann-Pick disease, type C1 Affected status: no Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000238437.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Publications: PubMed (5) PubMed: 16098014‚ 19744920‚ 10521297‚ 10480349‚ 18216017 Comment: The heterozygous variant in the NPC1 gene (c.3182T>C; p.Ile1061Thr) is considered pathogenic. This variant was seen in 29 alleles out of 120942 total interrogated at … (more) The heterozygous variant in the NPC1 gene (c.3182T>C; p.Ile1061Thr) is considered pathogenic. This variant was seen in 29 alleles out of 120942 total interrogated at this position in the ExAC database. This variant has been previously published in multiple individuals (Fernandez-Valero et al. 2005; PMID: 16098014; MIlat et al. 1999 PMID: 10521297; Yamamoto et al. 1999, PMID: 10480349) and functional studies performed show that the resulting protein fails to localize properly (Gelsthorpe et al 2008, PMID: 18216017). (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: SCV001453832.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	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: SCV001971474.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Mar 28, 2008)	no assertion criteria provided Method: literature only	NIEMANN-PICK DISEASE, TYPE C1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023259.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 30, 2024	Publications: PubMed (2) PubMed: 10521297‚ 18216017 Comment on evidence: In an initial study of 25 patients with type C1 Niemann-Pick disease (NPC1; 257220), Millat et al. (1999) identified a T-to-C transition at nucleotide 3182 … (more) In an initial study of 25 patients with type C1 Niemann-Pick disease (NPC1; 257220), Millat et al. (1999) identified a T-to-C transition at nucleotide 3182 of the NPC1 gene that led to an ile1061-to-thr substitution (I1061T) in 3 patients. The mutation, located in exon 21, affected a putative transmembrane domain of the protein. PCR-based tests with genomic DNA were used to survey 115 unrelated patients from around the world with all known clinical and biochemical phenotypes of the disease. The I1061T allele constituted 33 (14.3%) of the 230 disease-causing alleles and was never found in controls. The mutation was particularly frequent in patients with NPC from western Europe, especially France (11 of 62 alleles) and the U.K. (9 of 32 alleles), and in Hispanic patients whose roots were in the upper Rio Grande valley of the U.S. Millat et al. (1999) concluded that the I1061T mutation originated in Europe and that the high frequency in northern Rio Grande Hispanics resulted from a founder effect. All 7 unrelated patients who were homozygous for the mutation and their 7 affected sibs had a juvenile-onset neurologic disease and severe alterations of intracellular LDL-cholesterol processing. The mutation was not found (0 of 40 alleles) in patients with the severe infantile neurologic form of the disease. Using human fibroblasts homozygous for the I1061T mutation, Gelsthorpe et al. (2008) found that mutant NPC1 did not become fully glycosylated and had a half-life of 6.5 hours compared with 42 hours for wildtype NPC1. Treatment with chemical chaperones, growth at a cooler temperature, and proteasome inhibition increased mutant protein levels, suggesting it is targeted for ER-associated degradation (ERAD) due to protein misfolding. Overexpression of I1061T mutant NPC1 in NPC1-deficient cells resulted in endosomal localization of the mutant protein and complementation of the NPC mutant phenotype, likely due to a small proportion of the mutant protein that was able to fold correctly and escape ERAD. (less)
Pathogenic (Jul 16, 2024)	no assertion criteria provided Method: clinical testing	NPC1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004785140.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The NPC1 c.3182T>C variant is predicted to result in the amino acid substitution p.Ile1061Thr. This variant has been repeatedly documented as causative for Niemann-Pick disease … (more) The NPC1 c.3182T>C variant is predicted to result in the amino acid substitution p.Ile1061Thr. This variant has been repeatedly documented as causative for Niemann-Pick disease (Yamamoto et al. 1999. PubMed ID: 10480349; Gelsthorpe et al. 2008. PubMed ID: 18216017). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760424.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743369.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
not provided (-)	no classification provided Method: literature only	Niemann-Pick disease, type C1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040577.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 10521297‚ 16098014‚ 18216017‚ 20301473 BookShelf: NBK1296 BookShelf: NBK1296
click to load more click to collapse

Comment:

NM_000271.4(NPC1):c.3182T>C(I1061T) is classified as pathogenic in the context of Niemann-Pick disease, type C1. Sources cited for classification include the following: PMID 12401890, 10521290, 10480349, 21436030, 16098014, 11349231, 11754101, 18216017 and 22505584. Classification of NM_000271.4(NPC1):c.3182T>C(I1061T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Variant summary: NPC1 c.3182T>C (p.Ile1061Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251630 control chromosomes. This variant has been shown to be the most common mutation in NPC patients (Millat_1999). Functional study showed that the protein levels of NPC1 I1061T was significantly lower than the wild-type NPC1 due to misfolding (Gelsthorpe_2008). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant is one of the most common alterations identified in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 25149939, 20521171, 10480349). Functional characterization showed that the variant impairs proper protein localization and leads to proteasomal degradation in cell culture (PMID: 18216017, 25637190). The c.3182T>C (p.Ile1061Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.019% (53/282832) and thus is presumed to be rare. The c.3182T>C (p.Ile1061Thr) variant is predicted by in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3182T>C (p.Ile1061Thr) variant is classified as Pathogenic.

Comment:

In vitro studies of I1061T in human fibroblasts demonstrated that the protein fails to undergo normal glycosylation, leading to misfolding and degradation (Gelsthorpe et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28865947, 31589614, 31980526, 32138288, 31639011, 29476731, 29631617, 28776642, 28413817, 27923633, 25873482, 10480349, 25637190, 26019327, 24928400, 25149939, 10521297, 22505584, 23430855, 21436030, 20521171, 18216017, 25590979, 23521787, 26666848, 14639697, 28710748, 30487145, 30665703, 30556376)

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1061 of the NPC1 protein (p.Ile1061Thr). This variant is present in population databases (rs80358259, gnomAD 0.04%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 10521297, 16126423, 20521171, 25149939). It is commonly reported in individuals of American and Western European ancestry (PMID: 10521297). ClinVar contains an entry for this variant (Variation ID: 2967). 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%. Experimental studies have shown that this missense change affects NPC1 function (PMID: 18216017, 25637190, 26019327). For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type C1 Niemann-Pick disease (MIM#257220) and type D Niemann-Pick disease (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been observed amongst individuals carrying the same pathogenic variant (PMID: 32138288). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (53 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid c(SP) 0600 - Variant is located in the annotated Patched family domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed as compound heterozygous or homozygous in many individuals with Niemann-Pick disease type C1 (PMID: 35140266). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The heterozygous variant in the NPC1 gene (c.3182T>C; p.Ile1061Thr) is considered pathogenic. This variant was seen in 29 alleles out of 120942 total interrogated at this position in the ExAC database. This variant has been previously published in multiple individuals (Fernandez-Valero et al. 2005; PMID: 16098014; MIlat et al. 1999 PMID: 10521297; Yamamoto et al. 1999, PMID: 10480349) and functional studies performed show that the resulting protein fails to localize properly (Gelsthorpe et al 2008, PMID: 18216017).

Comment:

The NPC1 c.3182T>C variant is predicted to result in the amino acid substitution p.Ile1061Thr. This variant has been repeatedly documented as causative for Niemann-Pick disease (Yamamoto et al. 1999. PubMed ID: 10480349; Gelsthorpe et al. 2008. PubMed ID: 18216017). This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted 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
Correlation of age of onset and clinical severity in Niemann-Pick disease type C1 with lysosomal abnormalities and gene expression.	Baxter LL	Scientific reports	2022	PMID: 35140266
Generation of an iPSC line (AKOSi006-A) from fibroblasts of an NPC1 patient, carrying the homozygous mutation p.I1061T (c.3182 T > C) and a control iPSC line (AKOSi007-A) using a non-integrating Sendai virus system.	Völkner C	Stem cell research	2020	PMID: 33099109
Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants.	Dardis A	Journal of clinical medicine	2020	PMID: 32138288
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
New variant associated with Niemann-Pick disease type C: Neurological manifestations and biochemical, molecular, and cellular characterisation.	López de Frutos L	Neurologia	2020	PMID: 28865947
Niemann-Pick Disease Type C.	Adam MP	-	2020	PMID: 20301473
Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis.	Hastings C	Orphanet journal of rare diseases	2019	PMID: 31639011
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.	Wright CF	American journal of human genetics	2019	PMID: 30665703
Enrichment of pathogenic variants in genes associated with inborn errors of metabolism in psychiatric populations.	Sriretnakumar V	American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics	2019	PMID: 30556376
High-frequency actionable pathogenic exome variants in an average-risk cohort.	Rego S	Cold Spring Harbor molecular case studies	2018	PMID: 30487145
Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.	Sima N	Orphanet journal of rare diseases	2018	PMID: 29631617
Metabolic causes of nonimmune hydrops fetalis: A next-generation sequencing panel as a first-line investigation.	Sudrié-Arnaud B	Clinica chimica acta; international journal of clinical chemistry	2018	PMID: 29476731
Diagnosis of monogenic liver diseases in childhood by next-generation sequencing.	Stalke A	Clinical genetics	2018	PMID: 28776642
Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat.	Bowman EA	JIMD reports	2018	PMID: 28710748
Dataset in support of the generation of Niemann-Pick disease Type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation - Analysis of pluripotency and neuronal differentiation.	Peter F	Data in brief	2017	PMID: 28413817
Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons.	Trilck M	Brain research	2017	PMID: 27923633
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
A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele.	Praggastis M	The Journal of neuroscience : the official journal of the Society for Neuroscience	2015	PMID: 26019327
Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis.	Rauniyar N	Molecular & cellular proteomics : MCP	2015	PMID: 25873482
Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling.	Efthymiou AG	Stem cells translational medicine	2015	PMID: 25637190
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.	Zhu X	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590979
Cerebellar ataxia, vertical supranuclear gaze palsy, sensorineural deafness, epilepsy, dementia, and hallucinations in an adolescent male.	Tsao CY	Seminars in pediatric neurology	2014	PMID: 25149939
Structure-activity relationships of oxysterol-derived pharmacological chaperones for Niemann-Pick type C1 protein.	Ohgane K	Bioorganic & medicinal chemistry letters	2014	PMID: 24928400
Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking.	Zampieri S	JIMD reports	2012	PMID: 23430855
Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts.	Yu T	Human molecular genetics	2012	PMID: 22505584
Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts.	Pipalia NH	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 21436030
Loss of NPC1 function in a patient with a co-inherited novel insulin receptor mutation does not grossly modify the severity of the associated insulin resistance.	Kirk J	Journal of inherited metabolic disease	2010	PMID: 20521171
The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes.	Garver WS	Journal of lipid research	2010	PMID: 19744920
Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding.	Gelsthorpe ME	The Journal of biological chemistry	2008	PMID: 18216017
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
Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations.	Fernandez-Valero EM	Clinical genetics	2005	PMID: 16098014
Adult onset Niemann-Pick type C disease: A clinical, neuroimaging and molecular genetic study.	Battisti C	Movement disorders : official journal of the Movement Disorder Society	2003	PMID: 14639697
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
NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes.	Bauer P	Human mutation	2002	PMID: 11754101
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
Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype.	Millat G	American journal of human genetics	1999	PMID: 10521297
Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain.	Greer WL	American journal of human genetics	1999	PMID: 10521290
NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C.	Yamamoto T	Human genetics	1999	PMID: 10480349
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC1	-	-	-	-
click to load more click to collapse

Text-mined citations for rs80358259 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358259 ...