NM_000271.5(NPC1):c.3422T>G (p.Val1141Gly) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 6, 2021
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:: RCV001864018.4

Allele description [Variation Report for NM_000271.5(NPC1):c.3422T>G (p.Val1141Gly)]

NM_000271.5(NPC1):c.3422T>G (p.Val1141Gly)

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.3422T>G (p.Val1141Gly)

HGVS:

NC_000018.10:g.23535524A>C
NG_012795.1:g.56094T>G
NM_000271.5:c.3422T>GMANE SELECT
NP_000262.2:p.Val1141Gly
NC_000018.9:g.21115488A>C

Protein change:

V1141G

Links:

dbSNP: rs144725473

NCBI 1000 Genomes Browser:

rs144725473

Molecular consequence:

NM_000271.5:c.3422T>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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S41 family peptidase [Rhizobium croatiense]
S41 family peptidase [Rhizobium croatiense]
gi|2463813653|gnl|PRJNA939359|PYR68 0|gb|WET73573.1|

Protein
S41 family peptidase [Algibacter luteus]
S41 family peptidase [Algibacter luteus]
gi|2524566253|gnl|PRJNA914060|O5O44 5|gb|WJJ97035.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002118142	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 6, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12401890, 26666848, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002118142

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 6, 2021)

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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Niemann-Pick type C disease: mutations of NPC1 gene and evidence of abnormal expression of some mutant alleles in fibroblasts.

Tarugi P, Ballarini G, Bembi B, Battisti C, Palmeri S, Panzani F, Di Leo E, Martini C, Federico A, Calandra S.

J Lipid Res. 2002 Nov;43(11):1908-19.

PubMed [citation]

PMID:: 12401890

Observational cohort study of the natural history of Niemann-Pick disease type C in the UK: a 5-year update from the UK clinical database.

Imrie J, Heptinstall L, Knight S, Strong K.

BMC Neurol. 2015 Dec 15;15:257. doi: 10.1186/s12883-015-0511-1.

PubMed [citation]

PMID:: 26666848
PMCID:: PMC4678528

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002118142.3

#	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 valine with glycine at codon 1141 of the NPC1 protein (p.Val1141Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in partial deletion of exon 22 and introduces a new termination codon (PMID: 12401890). However the mRNA is not expected to undergo nonsense-mediated decay. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12401890, 26666848).

#	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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