NM_000271.5(NPC1):c.839del (p.Leu280fs) AND Niemann-Pick disease, type C1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Jul 22, 2021
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:: RCV000415044.3

Allele description [Variation Report for NM_000271.5(NPC1):c.839del (p.Leu280fs)]

NM_000271.5(NPC1):c.839del (p.Leu280fs)

Gene:

NPC1:NPC intracellular cholesterol transporter 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

18q11.2

Genomic location:

Preferred name:

NM_000271.5(NPC1):c.839del (p.Leu280fs)

HGVS:

NC_000018.10:g.23560277del
NG_012795.1:g.31345del
NM_000271.5:c.839delMANE SELECT
NP_000262.2:p.Leu280fs
NC_000018.9:g.21140241del
NM_000271.3:c.839delT
NM_000271.4:c.839delT

Protein change:

L280fs

Links:

dbSNP: rs1057518711

NCBI 1000 Genomes Browser:

rs1057518711

Molecular consequence:

NM_000271.5:c.839del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000328824	Baylor Genetics	no assertion criteria provided	Pathogenic (May 6, 2015)	maternal, germline	clinical testing
SCV000797211	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 16, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001810525	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	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

SCV000328824

Baylor Genetics

no assertion criteria provided

Pathogenic
(May 6, 2015)

maternal, germline

clinical testing

SCV000797211

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jan 16, 2018)

unknown

clinical testing

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

Citation Link,

SCV001810525

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 22, 2021)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	1	not provided	not provided	yes	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, Walkiewicz M, Bi W, Xiao R, Ding Y, Xia F, Beaudet AL, Muzny DM, Gibbs RA, Boerwinkle E, Eng CM, Sutton VR, Shaw CA, Plon SE, Yang Y, Lupski JR.

N Engl J Med. 2017 Jan 5;376(1):21-31. doi: 10.1056/NEJMoa1516767. Epub 2016 Dec 7.

PubMed [citation]

PMID:: 27959697
PMCID:: PMC5335876

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

Details of each submission

From Baylor Genetics, SCV000328824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	clinical testing (GTR000508680.4)	not provided
2	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	not provided

Description

Our laboratory reported dual molecular diagnoses inMTPAP (NM_018109.3, c.1468G>T) and NPC1 (NM_000271.3, c.839delT and c.2747A>G - phase unknown) in one individual with reported features of global developmental delay, developmental regression, central hypotonia, short stature, failure to thrive, familial neurodegenerative disease, cerebellar problems on brain MRI, absence like episodes, left hip dislocation, and constipation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided	(GTR000508680.4)	1	not provided	1	not provided
2	germline	unknown	not provided	not provided	not provided	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Counsyl, SCV000797211.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001810525.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 7, 2022

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