NM_000271.5(NPC1):c.1205_1208del (p.Phe402fs) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 4, 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:: RCV003605903.2

Allele description [Variation Report for NM_000271.5(NPC1):c.1205_1208del (p.Phe402fs)]

NM_000271.5(NPC1):c.1205_1208del (p.Phe402fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

18q11.2

Genomic location:

Preferred name:

NM_000271.5(NPC1):c.1205_1208del (p.Phe402fs)

HGVS:

NC_000018.10:g.23556364_23556367del
NG_012795.1:g.35254_35257del
NG_012795.2:g.35142_35145del
NM_000271.5:c.1205_1208delMANE SELECT
NP_000262.1:p.Phe402Serfs
NP_000262.2:p.Phe402fs
NC_000018.9:g.21136325_21136328del
NC_000018.9:g.21136328_21136331del
NM_000271.3:c.1202_1205delCTTT

Protein change:

F402fs

Molecular consequence:

NM_000271.5:c.1205_1208del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Niemann-Pick disease, type C1
Synonyms:: NIEMANN-PICK DISEASE WITHOUT SPHINGOMYELINASE DEFICIENCY; Niemann-Pick disease with cholesterol esterification block; Niemann-Pick disease, chronic neuronopathic form; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009757; MedGen: C3179455; Orphanet: 646; OMIM: 257220

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ARHGEF28 Rho guanine nucleotide exchange factor 28 [Homo sapiens]
ARHGEF28 Rho guanine nucleotide exchange factor 28 [Homo sapiens]
Gene ID:64283

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Gene Links for GEO Profiles (Select 109413295) (1)
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Gene Links for GEO Profiles (Select 109410235) (2)
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DYNC2I1 dynein 2 intermediate chain 1 [Homo sapiens]
DYNC2I1 dynein 2 intermediate chain 1 [Homo sapiens]
Gene ID:55112

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Gene Links for GEO Profiles (Select 109391045) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004373803	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 4, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9211850, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004373803

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 4, 2023)

germline

clinical testing

PubMed (2)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.

Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, Pentchev PG, Pavan WJ.

Science. 1997 Jul 11;277(5323):232-5.

PubMed [citation]

PMID:: 9211850

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004373803.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with NPC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe402Serfs*46) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850).

#	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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