VCV000021142.40 - ClinVar

NM_000271.5(NPC1):c.709C>T (p.Pro237Ser)

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.

(16)

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(1); Benign(6); Likely benign(2)

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.709C>T (p.Pro237Ser)

Variation ID: 21142 Accession: VCV000021142.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q11.2 18: 23560403 (GRCh38) [ NCBI UCSC ] 18: 21140367 (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	May 3, 2013	Feb 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000271.5:c.709C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000262.2:p.Pro237Ser	missense
NC_000018.10:g.23560403G>A
NC_000018.9:g.21140367G>A
NG_012795.1:g.31215C>T
	O15118:p.Pro237Ser

... more HGVS ... less HGVS

Protein change

P237S

Other names

NM_000271.4(NPC1):c.709C>T(p.Pro237Ser)

Canonical SPDI

NC_000018.10:23560402: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.

0.00459 (A)

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

1000 Genomes Project 30x 0.00453

1000 Genomes Project 0.00459

Trans-Omics for Precision Medicine (TOPMed) 0.00840

The Genome Aggregation Database (gnomAD), exomes 0.00988

Exome Aggregation Consortium (ExAC) 0.01046

The Genome Aggregation Database (gnomAD) 0.01055

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01153

Links

ClinGen: CA145972 UniProtKB: O15118#VAR_008817 dbSNP: rs80358251 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	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000020234.38
not specified	Benign (5)	criteria provided, multiple submitters, no conflicts	Jul 24, 2015	RCV000078486.27
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Mar 3, 2015	RCV000675580.23
Nasopharyngeal carcinoma	Benign (1)	criteria provided, single submitter	Sep 11, 2023	RCV003638614.1

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303391.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001865410.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Comment: This variant is associated with the following publications: (PMID: 32222928, 29631617, 28328115, 25842391, 10480349, 20981092, 12955717, 12554680, 22995991, 25497598, 20489167)
Benign (Jan 31, 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: SCV000770850.7 First in ClinVar: May 03, 2018 Last updated: Feb 20, 2024
Benign (Sep 11, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Nasopharyngeal carcinoma Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604562.4 First in ClinVar: Dec 06, 2016 Last updated: Feb 20, 2024
Benign (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Niemann-Pick disease, type C1 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803556.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Publications: PubMed (1) PubMed: 12554680 Comment: This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established … (more) This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:12554680). BS1 => Allele frequency is greater than expected for disorder (PMID:11182931). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. (less)
Benign (Jul 24, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110342.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 06, 2016	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: 4 Sex: mixed
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Niemann-Pick disease type C1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001283586.1 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001652757.1 First in ClinVar: May 29, 2021 Last updated: May 29, 2021	Sex: mixed
Likely benign (Aug 22, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Niemann-Pick disease type C1 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220553.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (14) PubMed: 12554680‚ 11182931‚ 12974729‚ 11333381‚ 23433426‚ 21550990‚ 12955717‚ 12408188‚ 20981092‚ 10480349‚ 20489167‚ 22995991‚ 12813037‚ 11349231
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956681.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (Sep 07, 2017)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Niemann-Pick disease, type C1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745716.1 First in ClinVar: May 30, 2015 Last updated: May 30, 2015
Likely benign (Feb 21, 2018)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801271.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797516.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807177.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921215.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
not provided (-)	no classification provided Method: literature only	Niemann-Pick disease, type C1 Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040580.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 11349231‚ 20301473 BookShelf: NBK1296 BookShelf: NBK1296
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Comment:

This variant is interpreted as a Benign, for Niemann-Pick disease, type C1, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:12554680). BS1 => Allele frequency is greater than expected for disorder (PMID:11182931). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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
Niemann-Pick Disease Type C.	Adam MP	-	2020	PMID: 20301473
Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators.	Stampfer M	Orphanet journal of rare diseases	2013	PMID: 23433426
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Altered vitamin E status in Niemann-Pick type C disease.	Ulatowski L	Journal of lipid research	2011	PMID: 21550990
A map of human genome variation from population-scale sequencing.	1000 Genomes Project Consortium	Nature	2010	PMID: 20981092
Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels.	Uronen RL	Arteriosclerosis, thrombosis, and vascular biology	2010	PMID: 20489167
Niemann-Pick disease type C.	Vanier MT	Clinical genetics	2003	PMID: 12974729
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
Impaired ABCA1-dependent lipid efflux and hypoalphalipoproteinemia in human Niemann-Pick type C disease.	Choi HY	The Journal of biological chemistry	2003	PMID: 12813037
Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease.	Blom TS	Human molecular genetics	2003	PMID: 12554680
Identification of novel mutations in the NPC1 gene in German patients with Niemann-Pick C disease.	Kaminski WE	Journal of inherited metabolic disease	2002	PMID: 12408188
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: 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
Genotype-phenotype relationship of Niemann-Pick disease type C: a possible correlation between clinical onset and levels of NPC1 protein in isolated skin fibroblasts.	Yamamoto T	Journal of medical genetics	2000	PMID: 11182931
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	-	-	-	-
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Text-mined citations for rs80358251 ...

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.709C>T (p.Pro237Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358251 ...