NM_000271.5(NPC1):c.2713C>T (p.Gln905Ter) AND Niemann-Pick disease, type C1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Sep 5, 2018
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:: RCV000474466.8

Allele description [Variation Report for NM_000271.5(NPC1):c.2713C>T (p.Gln905Ter)]

NM_000271.5(NPC1):c.2713C>T (p.Gln905Ter)

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.2713C>T (p.Gln905Ter)

HGVS:

NC_000018.10:g.23539893G>A
NG_012795.1:g.51725C>T
NM_000271.5:c.2713C>TMANE SELECT
NP_000262.2:p.Gln905Ter
NC_000018.9:g.21119857G>A
NM_000271.4:c.2713C>T

Protein change:

Q905*

Links:

dbSNP: rs917070773

NCBI 1000 Genomes Browser:

rs917070773

Molecular consequence:

NM_000271.5:c.2713C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000538195	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000650841	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 5, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19252935, 23433426, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000538195

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 16, 2016)

germline

clinical testing

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

SCV000650841

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 5, 2018)

germline

clinical testing

PubMed (3)
[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	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations.

Fancello T, Dardis A, Rosano C, Tarugi P, Tappino B, Zampieri S, Pinotti E, Corsolini F, Fecarotta S, D'Amico A, Di Rocco M, Uziel G, Calandra S, Bembi B, Filocamo M.

Neurogenetics. 2009 Jul;10(3):229-39. doi: 10.1007/s10048-009-0175-3. Epub 2009 Feb 28.

PubMed [citation]

PMID:: 19252935

See all PubMed Citations (4)

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV000538195.1

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

Description

The c.2713 C>T (p.Gln905Ter) in the NPC1 gene is a novel stop-gain variant that is predicted to result in premature truncation of the NPC1 protein. This variant was not found in the 1000 Genomes, Exome Variant Server (EVS) or ExAC databases. Thus, it is presumed to be rare. The Gln905 amino acid residue is highly conserved and insilico algorithms predict the variant to be pathogenic. Based on the combined evidence, this variant is classified as likely pathogenic for Niemann-Pick disease, type C1.

#	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		1	not provided	not provided	not provided

From Invitae, SCV000650841.5

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

Description

For these reasons, this variant has been classified as Pathogenic. While this variant has not been reported in the literature, loss-of-function variants in NPC1 are known to be pathogenic (PMID: 19252935, 23433426). This sequence change creates a premature translational stop signal at codon 905 (p.Gln905*) of the NPC1 gene. It is expected to result in an absent or disrupted protein product.

#	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 5, 2024

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