NM_000271.5(NPC1):c.1672G>T (p.Ala558Ser) AND Niemann-Pick disease, type C1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Nov 8, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001127620.8

Allele description [Variation Report for NM_000271.5(NPC1):c.1672G>T (p.Ala558Ser)]

NM_000271.5(NPC1):c.1672G>T (p.Ala558Ser)

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.1672G>T (p.Ala558Ser)

HGVS:

NC_000018.10:g.23548091C>A
NG_012795.1:g.43527G>T
NM_000271.5:c.1672G>TMANE SELECT
NP_000262.2:p.Ala558Ser
NC_000018.9:g.21128055C>A
NC_000018.9:g.21128055C>A
NM_000271.4:c.1672G>T

Protein change:

A558S

Links:

dbSNP: rs201156397

NCBI 1000 Genomes Browser:

rs201156397

Molecular consequence:

NM_000271.5:c.1672G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001286949	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Sep 14, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23427322, 22269206, 24386122 Citation Link,
SCV003443335	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24386122, 22269206, 23427322, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001286949

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Sep 14, 2017)

germline

clinical testing

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

Citation Link,

SCV003443335

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (4)
[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 C disease gene mutations and age-related neurodegenerative disorders.

Zech M, Nübling G, Castrop F, Jochim A, Schulte EC, Mollenhauer B, Lichtner P, Peters A, Gieger C, Marquardt T, Vanier MT, Latour P, Klünemann H, Trenkwalder C, Diehl-Schmid J, Perneczky R, Meitinger T, Oexle K, Haslinger B, Lorenzl S, Winkelmann J.

PLoS One. 2013;8(12):e82879. doi: 10.1371/journal.pone.0082879.

PubMed [citation]

PMID:: 24386122
PMCID:: PMC3875432

Low ceruloplasmin in a patient with Niemann-Pick type C disease.

Connemann BJ, Gahr M, Schmid M, Runz H, Freudenmann RW.

J Clin Neurosci. 2012 Apr;19(4):620-1. doi: 10.1016/j.jocn.2011.05.038. Epub 2012 Jan 24.

PubMed [citation]

PMID:: 22269206

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001286949.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003443335.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 558 of the NPC1 protein (p.Ala558Ser). This variant is present in population databases (rs201156397, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease type C (PMID: 24386122). ClinVar contains an entry for this variant (Variation ID: 891970). 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.Ala558 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22269206, 23427322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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