NM_006432.5(NPC2):c.295T>C (p.Cys99Arg) AND Niemann-Pick disease, type C2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 3, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000020646.7

Allele description [Variation Report for NM_006432.5(NPC2):c.295T>C (p.Cys99Arg)]

NM_006432.5(NPC2):c.295T>C (p.Cys99Arg)

Gene:

NPC2:NPC intracellular cholesterol transporter 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.3

Genomic location:

Preferred name:

NM_006432.5(NPC2):c.295T>C (p.Cys99Arg)

HGVS:

NC_000014.9:g.74484483A>G
NG_007117.1:g.13899T>C
NM_001363688.1:c.295T>C
NM_001375440.1:c.295T>C
NM_006432.5:c.295T>CMANE SELECT
NP_001350617.1:p.Cys99Arg
NP_001362369.1:p.Cys99Arg
NP_006423.1:p.Cys99Arg
NC_000014.8:g.74951186A>G
NM_006432.3:c.295T>C
P61916:p.Cys99Arg

Protein change:

C99R

Links:

UniProtKB: P61916#VAR_043306; dbSNP: rs80358264

NCBI 1000 Genomes Browser:

rs80358264

Molecular consequence:

NM_001363688.1:c.295T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001375440.1:c.295T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006432.5:c.295T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Niemann-Pick disease, type C2 (NPC2)
Identifiers:: MONDO: MONDO:0011873; MedGen: C1843366; Orphanet: 646; OMIM: 607625

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000041171	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 15937921, 20301473
SCV001406857	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22676771, 15937921, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000041171

GeneReviews

no classification provided

not provided

unknown

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV001406857

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Niemann-Pick Disease Type C.

Patterson M.

2000 Jan 26 [updated 2020 Dec 10]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301473

Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C.

Héron B, Valayannopoulos V, Baruteau J, Chabrol B, Ogier H, Latour P, Dobbelaere D, Eyer D, Labarthe F, Maurey H, Cuisset JM, de Villemeur TB, Sedel F, Vanier MT.

Orphanet J Rare Dis. 2012 Jun 7;7:36. doi: 10.1186/1750-1172-7-36.

PubMed [citation]

PMID:: 22676771
PMCID:: PMC3465012

See all PubMed Citations (4)

Details of each submission

From GeneReviews, SCV000041171.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	not provided	not provided	Assert pathogenicity		not provided	not provided	not provided	not provided

From Invitae, SCV001406857.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 99 of the NPC2 protein (p.Cys99Arg). This variant is present in population databases (rs80358264, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 15937921, 22676771). ClinVar contains an entry for this variant (Variation ID: 21458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NPC2 function (PMID: 15937921). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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