NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln) AND Niemann-Pick disease, type C

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 1, 2016
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:: RCV000588149.2

Allele description [Variation Report for NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln)]

NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln)

Gene:

NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q11.2

Genomic location:

Preferred name:

NM_000271.5(NPC1):c.1211G>A (p.Arg404Gln)

HGVS:

NC_000018.10:g.23556358C>T
NG_012795.1:g.35260G>A
NM_000271.5:c.1211G>AMANE SELECT
NP_000262.2:p.Arg404Gln
NC_000018.9:g.21136322C>T
NM_000271.4:c.1211G>A
O15118:p.Arg404Gln

Protein change:

R404Q

Links:

UniProtKB: O15118#VAR_043194; dbSNP: rs139751448

NCBI 1000 Genomes Browser:

rs139751448

Molecular consequence:

NM_000271.5:c.1211G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Niemann-Pick disease, type C (NPC)
Identifiers:: MONDO: MONDO:0018982; MedGen: C0220756

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696414	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 1, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11349231, 26981555, 12955717, 11333381, 11545687, 19744920 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000696414

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 1, 2016)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Niemann-Pick C variant detection by altered sphingolipid trafficking and correlation with mutations within a specific domain of NPC1.

Sun X, Marks DL, Park WD, Wheatley CL, Puri V, O'Brien JF, Kraft DL, Lundquist PA, Patterson MC, Pagano RE, Snow K.

Am J Hum Genet. 2001 Jun;68(6):1361-72. Epub 2001 May 9.

PubMed [citation]

PMID:: 11349231
PMCID:: PMC1226123

Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening.

Reunert J, Fobker M, Kannenberg F, Du Chesne I, Plate M, Wellhausen J, Rust S, Marquardt T.

EBioMedicine. 2016 Feb;4:170-5. doi: 10.1016/j.ebiom.2015.12.018.

PubMed [citation]

PMID:: 26981555
PMCID:: PMC4776073

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696414.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: The c.1211G>A (p.Arg404Gln) in NPC1 gene is a missense change that alters a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. These predictions were also confirmed by functional studies, where very low esterification values were found in fibroblasts of a patient homozygous for R404Q. The variant is present in the large control population dataset of ExAC at a frequency 0.000041 (5/121346 chrs tested), which does not exceed the estimated maximal expected allele frequency of a pathogenic variant (0.0028). The variant was identified in multiple affected individuals with established dx of classical NPC. Lastly, multiple reputable diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was 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: Sep 29, 2024

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