NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs) AND Niemann-Pick disease, type C

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 9, 2020
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:: RCV000781673.7

Allele description [Variation Report for NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs)]

NM_000271.5(NPC1):c.2972_2973del (p.Gln991fs)

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.2972_2973del (p.Gln991fs)

HGVS:

NC_000018.10:g.23538610_23538611del
NG_012795.1:g.53007_53008del
NM_000271.5:c.2972_2973delMANE SELECT
NP_000262.2:p.Gln991fs
NC_000018.9:g.21118574_21118575del
NC_000018.9:g.21118574_21118575delCT
NM_000271.4:c.2972_2973del
NM_000271.4:c.2972_2973delAG

Protein change:

Q991fs

Links:

dbSNP: rs756815030

NCBI 1000 Genomes Browser:

rs756815030

Molecular consequence:

NM_000271.5:c.2972_2973del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Niemann-Pick disease, type C (NPC)
Identifiers:: MONDO: MONDO:0018982; MedGen: C0220756

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919897	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 19, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16126423, 26830282, 10521290, 19252935 Citation Link,
SCV001653013	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jun 9, 2020)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16086131, 10521290, 26666848, 12401890, 23427322, 24915861, 26830282, 16126423, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919897

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 19, 2018)

germline

clinical testing

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

Citation Link,

SCV001653013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jun 9, 2020)

germline

clinical testing

PubMed (9)
[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	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Lung involvement in Niemann-Pick disease type C1: improvement with bronchoalveolar lavage.

Palmeri S, Tarugi P, Sicurelli F, Buccoliero R, Malandrini A, De Santi MM, Marcianò G, Battisti C, Dotti MT, Calandra S, Federico A.

Neurol Sci. 2005 Jul;26(3):171-3.

PubMed [citation]

PMID:: 16086131

See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919897.1

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

Description

Variant summary: NPC1 c.2972_2973delAG (p.Gln991ArgfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3742_3745delCTCA (p.Leu1248fsX3)). The variant allele was found at a frequency of 4.7e-05 in 277230 control chromosomes. This frequency is not higher than expected for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (4.7e-05 vs 0.0028), allowing no conclusion about variant significance. c.2972_2973delAG has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C, including several homozygous patients who are severely affected (e.g. Millat_2005, Fancello_2009, Elmonem_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001653013.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Gln991ArgfsX15 variant in NPC1 has been reported in at least 8 individuals with Neimann-Pick Type C, in the compound heterozygous (5), homozygous (2) or heterozygous state (1) (Greer 1999 PMID: 10521290, Tarugi 2002 PMID: 12401890, Palmeri 2005 PMID: 16086131, Millat 2005 PMID: 16126423, Schicks 2013 PMID: 23427322, Imrie 2015 PMID: 26666848, Elmonem 2016 PMID: 26830282). It has also been identified in 0.01% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 188932). This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 991 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the NPC1 gene is an established disease mechanism in autosomal recessive Niemann-Pick Type C Disease. In vitro functional studies provide some evidence that this variant does impacts protein function (Tarugi 2002 PMID: 12401890); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Niemann-Pick Type C Disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting, PS3_Supporting.

#	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		1	not provided	1	not provided

Last Updated: Oct 20, 2024

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