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NM_000271.5(NPC1):c.1415T>C (p.Leu472Pro) AND Niemann-Pick disease, type C1

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 5, 2022
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:
RCV002019754.6

Allele description [Variation Report for NM_000271.5(NPC1):c.1415T>C (p.Leu472Pro)]

NM_000271.5(NPC1):c.1415T>C (p.Leu472Pro)

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.1415T>C (p.Leu472Pro)
HGVS:
  • NC_000018.10:g.23554896A>G
  • NG_012795.1:g.36722T>C
  • NM_000271.5:c.1415T>CMANE SELECT
  • NP_000262.2:p.Leu472Pro
  • NC_000018.9:g.21134860A>G
Protein change:
L472P
Links:
dbSNP: rs2145447843
NCBI 1000 Genomes Browser:
rs2145447843
Molecular consequence:
  • NM_000271.5:c.1415T>C - 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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002285427Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Feb 5, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants.

Dardis A, Zampieri S, Gellera C, Carrozzo R, Cattarossi S, Peruzzo P, Dariol R, Sechi A, Deodato F, Caccia C, Verrigni D, Gasperini S, Fiumara A, Fecarotta S, Carecchio M, Filosto M, Santoro L, Borroni B, Bordugo A, Brancati F, Russo CV, Di Rocco M, et al.

J Clin Med. 2020 Mar 3;9(3). doi:pii: E679. 10.3390/jcm9030679.

PubMed [citation]
PMID:
32138288
PMCID:
PMC7141276

High-content imaging and structure-based predictions reveal functional differences between Niemann-Pick C1 variants.

Vanharanta L, Peränen J, Pfisterer SG, Enkavi G, Vattulainen I, Ikonen E.

Traffic. 2020 May;21(5):386-397. doi: 10.1111/tra.12727. Epub 2020 Apr 5.

PubMed [citation]
PMID:
32144825
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002285427.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Leu472 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 32138288), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects NPC1 function (PMID: 32144825). 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 Type C (PMID: 28883878). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 472 of the NPC1 protein (p.Leu472Pro).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024