NM_000271.5(NPC1):c.3467A>G (p.Asn1156Ser) AND Niemann-Pick disease, type C1

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

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 21, 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:: RCV000003093.11

Allele description

NM_000271.5(NPC1):c.3467A>G (p.Asn1156Ser)

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.3467A>G (p.Asn1156Ser)

HGVS:

NC_000018.10:g.23535479T>C
NG_012795.1:g.56139A>G
NM_000271.5:c.3467A>GMANE SELECT
NP_000262.2:p.Asn1156Ser
NC_000018.9:g.21115443T>C
NM_000271.4:c.3467A>G
O15118:p.Asn1156Ser

Protein change:

N1156S; ASN1156SER

Links:

UniProtKB: O15118#VAR_008838; OMIM: 607623.0003; dbSNP: rs28942105

NCBI 1000 Genomes Browser:

rs28942105

Molecular consequence:

NM_000271.5:c.3467A>G - 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
SCV000023251	OMIM	no assertion criteria provided	Pathogenic (Jul 11, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000297806	Shendure Lab, University of Washington	no assertion criteria provided	Pathogenic (Aug 1, 2016)	germline	clinical testing
SCV000957635	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 21, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 28710748, 9211849, 16098014, 17160617, 23430855, 26666848, 27900365, 28492532
SCV001163433	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Citations

PubMed

Longitudinal Changes in White Matter Fractional Anisotropy in Adult-Onset Niemann-Pick Disease Type C Patients Treated with Miglustat.

Bowman EA, Velakoulis D, Desmond P, Walterfang M.

JIMD Rep. 2018;39:39-43. doi: 10.1007/8904_2017_42. Epub 2017 Jul 15.

PubMed [citation]

PMID:: 28710748
PMCID:: PMC5953894

Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.

Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, et al.

Science. 1997 Jul 11;277(5323):228-31.

PubMed [citation]

PMID:: 9211849

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000023251.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In each of 2 unrelated patients with Niemann-Pick disease (NPC1; 257220), Carstea et al. (1997) found compound heterozygosity at the NPC1 locus with one of the mutations being a 3467A-G transition, resulting in an asn1156-to-ser amino acid substitution in the NPC1 protein. The authors noted that asn1156 is conserved in human, mouse, C. elegans, and S. cerevisiae orthologs of NPC1.

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

From Shendure Lab, University of Washington, SCV000297806.1

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

Description

patient had late-onset NPC

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

From Invitae, SCV000957635.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NPC1 protein (p.Asn1156Ser). This variant is present in population databases (rs28942105, gnomAD 0.004%). This missense change has been observed in individuals with Niemann-Pick type C (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365, 28710748). ClinVar contains an entry for this variant (Variation ID: 2959). 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.Asn1156 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 9211849, 16098014, 17160617, 23430855, 26666848, 27900365), 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 Baylor Genetics, SCV001163433.1

#	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 30, 2024

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