NM_000271.5(NPC1):c.3379_3380del (p.Met1127fs) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 4, 2020
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:: RCV001064156.7

Allele description [Variation Report for NM_000271.5(NPC1):c.3379_3380del (p.Met1127fs)]

NM_000271.5(NPC1):c.3379_3380del (p.Met1127fs)

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.3379_3380del (p.Met1127fs)

HGVS:

NC_000018.10:g.23535566_23535567del
NG_012795.1:g.56051_56052del
NM_000271.5:c.3379_3380delMANE SELECT
NP_000262.2:p.Met1127fs
NC_000018.9:g.21115530_21115531del
NM_000271.4:c.3379_3380del

Protein change:

M1127fs

Links:

dbSNP: rs2058616798

NCBI 1000 Genomes Browser:

rs2058616798

Molecular consequence:

NM_000271.5:c.3379_3380del - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001229038	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10521290, 11479732, 12401890, 25425405, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001229038

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2020)

germline

clinical testing

PubMed (5)
[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

Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain.

Greer WL, Dobson MJ, Girouard GS, Byers DM, Riddell DC, Neumann PE.

Am J Hum Genet. 1999 Nov;65(5):1252-60.

PubMed [citation]

PMID:: 10521290
PMCID:: PMC1288277

Niemann-Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol trafficking alterations.

Ribeiro I, Marcão A, Amaral O, Sá Miranda MC, Vanier MT, Millat G.

Hum Genet. 2001 Jul;109(1):24-32.

PubMed [citation]

PMID:: 11479732

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001229038.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the NPC1 protein. Other variant(s) that disrupt this region (p.Arg1173Lysfs*85, p.Phe1199Leufs*43) have been determined to be pathogenic (PMID: 10521290, 11479732, 12401890, 25425405, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 858308). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the NPC1 gene (p.Met1127Valfs*130). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acids of the NPC1 protein.

#	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: Feb 28, 2024

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