NM_000271.5(NPC1):c.1843C>T (p.Arg615Cys) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000685980.9

Allele description [Variation Report for NM_000271.5(NPC1):c.1843C>T (p.Arg615Cys)]

NM_000271.5(NPC1):c.1843C>T (p.Arg615Cys)

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.1843C>T (p.Arg615Cys)

HGVS:

NC_000018.10:g.23545064G>A
NG_012795.1:g.46554C>T
NM_000271.5:c.1843C>TMANE SELECT
NP_000262.2:p.Arg615Cys
NC_000018.9:g.21125028G>A
NM_000271.4:c.1843C>T

Protein change:

R615C

Links:

dbSNP: rs745777805

NCBI 1000 Genomes Browser:

rs745777805

Molecular consequence:

NM_000271.5:c.1843C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000813483	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26666848, 17160617, 28492532
SCV001554477	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000813483

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 2, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001554477

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 7, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

The natural history of Niemann-Pick disease type C in the UK.

Imrie J, Dasgupta S, Besley GT, Harris C, Heptinstall L, Knight S, Vanier MT, Fensom AH, Ward C, Jacklin E, Whitehouse C, Wraith JE.

J Inherit Metab Dis. 2007 Feb;30(1):51-9. Epub 2006 Dec 11. Erratum in: J Inherit Metab Dis. 2007 Oct;30(5):833.

PubMed [citation]

PMID:: 17160617

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000813483.6

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 615 of the NPC1 protein (p.Arg615Cys). This variant is present in population databases (rs745777805, gnomAD 0.01%). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 26666848). ClinVar contains an entry for this variant (Variation ID: 566223). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg615 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 17160617), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been 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

From Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SCV001554477.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	no	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	discovery		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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