NM_000271.5(NPC1):c.2692G>A (p.Asp898Asn) AND Niemann-Pick disease, type C1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 9, 2022
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:: RCV000779242.11

Allele description [Variation Report for NM_000271.5(NPC1):c.2692G>A (p.Asp898Asn)]

NM_000271.5(NPC1):c.2692G>A (p.Asp898Asn)

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.2692G>A (p.Asp898Asn)

HGVS:

NC_000018.10:g.23539914C>T
NG_012795.1:g.51704G>A
NM_000271.5:c.2692G>AMANE SELECT
NP_000262.2:p.Asp898Asn
NC_000018.9:g.21119878C>T
NM_000271.4:c.2692G>A

Protein change:

D898N

Links:

dbSNP: rs528841924

NCBI 1000 Genomes Browser:

rs528841924

Molecular consequence:

NM_000271.5:c.2692G>A - 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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Ephb1 [Microtus fortis]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915798	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Nov 19, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001497275	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 9, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25425405, 28492532
SCV002095186	Natera, Inc.	no assertion criteria provided	Uncertain significance (Oct 6, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000915798

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Nov 19, 2018)

germline

clinical testing

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

Citation Link,

SCV001497275

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 9, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002095186

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Oct 6, 2020)

germline

clinical testing

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

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study.

Abela L, Plecko B, Palla A, Burda P, Nuoffer JM, Ballhausen D, Rohrbach M.

Orphanet J Rare Dis. 2014 Nov 26;9:176. doi: 10.1186/s13023-014-0176-7.

PubMed [citation]

PMID:: 25425405
PMCID:: PMC4253629

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 Illumina Laboratory Services, Illumina, SCV000915798.1

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

Description

The NPC1 c.2692G>A (p.Asp898Asn) variant has been described in a single study in which it was found in a compound heterozygous state with a frameshift variant in one individual with Niemann-Pick disease (Abela et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.000047 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp898Asn variant is classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease, type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Invitae, SCV001497275.3

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 898 of the NPC1 protein (p.Asp898Asn). This variant is present in population databases (rs528841924, gnomAD 0.006%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 25425405). ClinVar contains an entry for this variant (Variation ID: 440008). 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 not expected to disrupt NPC1 protein function. 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.

#	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 Natera, Inc., SCV002095186.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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: Dec 24, 2023

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