NM_000271.5(NPC1):c.1672G>A (p.Ala558Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003331276.1

Allele description [Variation Report for NM_000271.5(NPC1):c.1672G>A (p.Ala558Thr)]

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004037977	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 18, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23433426, 28808920, 22269206, 23427322 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004037977

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 18, 2023)

germline

clinical testing

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

Citation Link

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

Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators.

Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, Mengel E, Fischer C, Runz H.

Orphanet J Rare Dis. 2013 Feb 22;8:35. doi: 10.1186/1750-1172-8-35.

PubMed [citation]

PMID:: 23433426
PMCID:: PMC3649939

Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member.

Topçu M, Aktas D, Öztoprak M, Mungan NÖ, Yuce A, Alikasifoglu M.

Mol Diagn Ther. 2017 Dec;21(6):643-651. doi: 10.1007/s40291-017-0293-9.

PubMed [citation]

PMID:: 28808920

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037977.1

#	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.1672G>A (p.Ala558Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes (gnomAD). c.1672G>A has been reported in the literature in individuals affected with Niemann-Pick Disease Type C and and cerebellar ataxia (examples: Connemann_2012, Stampfer_2013, Schicks_2013, and Topcu_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22269206, 23427322, 23433426, 28808920). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly 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

Last Updated: Sep 29, 2024

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