NM_000271.5(NPC1):c.1672G>A (p.Ala558Thr) AND Niemann-Pick disease, type C1

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Dec 19, 2023
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:: RCV002038330.6

Allele description

NM_000271.5(NPC1):c.1672G>A (p.Ala558Thr)

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>A (p.Ala558Thr)

HGVS:

NC_000018.10:g.23548091C>T
NG_012795.1:g.43527G>A
NM_000271.5:c.1672G>AMANE SELECT
NP_000262.2:p.Ala558Thr
NC_000018.9:g.21128055C>T
NM_000271.4:c.1672G>A

Protein change:

A558T

Links:

dbSNP: rs201156397

NCBI 1000 Genomes Browser:

rs201156397

Molecular consequence:

NM_000271.5:c.1672G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002317398	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22269206, 23427322, 32289814, 28492532
SCV003815176	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 6, 2022)	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

SCV002317398

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2023)

germline

clinical testing

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

SCV003815176

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 6, 2022)

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

Citations

PubMed

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

Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy.

Schicks J, Müller Vom Hagen J, Bauer P, Beck-Wödl S, Biskup S, Krägeloh-Mann I, Schöls L, Synofzik M.

Neurology. 2013 Mar 19;80(12):1169-70. doi: 10.1212/WNL.0b013e31828869f9. Epub 2013 Feb 20. No abstract available.

PubMed [citation]

PMID:: 23427322

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV002317398.3

#	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 threonine, which is neutral and polar, at codon 558 of the NPC1 protein (p.Ala558Thr). This variant is present in population databases (rs201156397, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick disease type C (PMID: 22269206, 23427322). ClinVar contains an entry for this variant (Variation ID: 1519574). 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 observed in individuals with NPC1-related conditions (PMID: 32289814), 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 Revvity Omics, Revvity, SCV003815176.2

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

#	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: Mar 16, 2024

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