VCV000183281.36 - ClinVar

NM_006432.5(NPC2):c.88G>A (p.Val30Met)

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.

(15)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006432.5(NPC2):c.88G>A (p.Val30Met)

Variation ID: 183281 Accession: VCV000183281.36

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.3 14: 74486431 (GRCh38) [ NCBI UCSC ] 14: 74953134 (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	Mar 16, 2015	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006432.5:c.88G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006423.1:p.Val30Met	missense
NM_001363688.1:c.88G>A	NP_001350617.1:p.Val30Met	missense
NM_001375440.1:c.88G>A	NP_001362369.1:p.Val30Met	missense
NC_000014.9:g.74486431C>T
NC_000014.8:g.74953134C>T
NG_007117.1:g.11951G>A
	P61916:p.Val30Met

... more HGVS ... less HGVS

Protein change

V30M

Other names

Canonical SPDI

NC_000014.9:74486430:C:T

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.

0.00100 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00213

Exome Aggregation Consortium (ExAC) 0.00311

1000 Genomes Project 30x 0.00094

1000 Genomes Project 0.00100

The Genome Aggregation Database (gnomAD) 0.00122

Trans-Omics for Precision Medicine (TOPMed) 0.00134

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00192

Links

ClinGen: CA249909 UniProtKB: P61916#VAR_043303 dbSNP: rs151220873 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.
ACYP1		-	-	GRCh38 GRCh37	1	20
NPC2		-	-	GRCh38 GRCh37	260	289

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.
Brain atrophy Global developmental delay Microcephaly Seizure	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2014	RCV000162102.3
not specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Jul 6, 2022	RCV000362578.5
not provided	Likely benign (8)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000675984.24
Niemann-Pick disease, type C2	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001080727.11

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.
Benign (Aug 25, 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: SCV000331094.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC2 Number of individuals with the variant: 2 Sex: mixed
Benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001716365.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Sex: mixed
Likely benign (Oct 06, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001782622.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Comment: This variant is associated with the following publications: (PMID: 32858489, 15465422, 30556376, 15937921, 12955717, 25764212, 24386122, 21228398, 27792009, 25558065, 27884173, 25099932)
Benign (Jul 06, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570814.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (4) PubMed: 25764212‚ 12955717‚ 15937921‚ 25558065 Comment: Variant summary: NPC2 c.88G>A (p.Val30Met) results in a conservative amino acid change located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Four … (more) Variant summary: NPC2 c.88G>A (p.Val30Met) results in a conservative amino acid change located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 207464 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.88G>A with Niemann-Pick Disease Type C has been reported in the literature. A functional study examining the expression and localization of NPC2 missense variants in human fibroblasts found no biological abnormalities in cells expressing this variant, suggesting it does not strongly impact protein function (Chikh_2005). Seven assessments for this variant have been submitted to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. (less)
Likely benign (Oct 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Niemann-Pick disease, type C2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002806058.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Niemann-Pick disease, type C2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001013996.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005212549.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135068.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Likely benign (Jul 01, 2024)	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: SCV004136891.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: NPC2: BP4, BS2 Number of individuals with the variant: 5
Likely pathogenic (Dec 01, 2014)	no assertion criteria provided (research) Method: research	Global developmental delay Microcephaly Epilepsy Brain atrophy Affected status: yes Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV000196387.1 First in ClinVar: Mar 16, 2015 Last updated: Mar 16, 2015	Publications: PubMed (1) PubMed: 25558065
Likely benign (Dec 19, 2017)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000801716.1 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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741169.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (Apr 18, 2020)	no assertion criteria provided Method: clinical testing	Niemann-Pick disease type C2 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461635.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	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: SCV001807119.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Likely benign (-)	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: SCV001968707.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

Variant summary: NPC2 c.88G>A (p.Val30Met) results in a conservative amino acid change located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 207464 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.88G>A with Niemann-Pick Disease Type C has been reported in the literature. A functional study examining the expression and localization of NPC2 missense variants in human fibroblasts found no biological abnormalities in cells expressing this variant, suggesting it does not strongly impact protein function (Chikh_2005). Seven assessments for this variant have been submitted to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign.

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
High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets.	Wassif CA	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 25764212
Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.	Alazami AM	Cell reports	2015	PMID: 25558065
Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations.	Chikh K	Human mutation	2005	PMID: 15937921
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NPC2	-	-	-	-

Text-mined citations for rs151220873 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_006432.5(NPC2):c.88G>A (p.Val30Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs151220873 ...