NM_000235.4(LIPA):c.894G>A (p.Gln298=) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 16, 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:: RCV002372140.4

Allele description [Variation Report for NM_000235.4(LIPA):c.894G>A (p.Gln298=)]

NM_000235.4(LIPA):c.894G>A (p.Gln298=)

Gene:

LIPA:lipase A, lysosomal acid type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_000235.4(LIPA):c.894G>A (p.Gln298=)

Other names:

934G>A; E8SJ; p.Gln298=

HGVS:

NC_000010.11:g.89222511C>T
NG_008194.1:g.34393G>A
NM_000235.4:c.894G>AMANE SELECT
NM_001127605.3:c.894G>A
NM_001288979.2:c.546G>A
NP_000226.2:p.Gln298=
NP_001121077.1:p.Gln298=
NP_001275908.1:p.Gln182=
NC_000010.10:g.90982268C>T
NM_000235.2:c.894G>A
NM_000235.3:c.894G>A
NM_001127605.1:c.894G>A
NP_001121077.1:p.=

Nucleotide change:

934G-A

Links:

OMIM: 613497.0002; dbSNP: rs116928232

NCBI 1000 Genomes Browser:

rs116928232

Molecular consequence:

NM_000235.4:c.894G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001127605.3:c.894G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001288979.2:c.546G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

exon loss [PubMedVariation Ontology: 0381]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002683966	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 16, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 10562460, 16255772, 21757691, 22227072, 22795295, 23424026, 24072694, 25722898, 25852113, 26350820, 28502505, 28502515, 7751811, 8254026, 8617513 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002683966

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 16, 2023)

germline

clinical testing

PubMed (15)
[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

Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease.

Anderson RA, Bryson GM, Parks JS.

Mol Genet Metab. 1999 Nov;68(3):333-45.

PubMed [citation]

PMID:: 10562460

Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease.

Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA.

Lipids Health Dis. 2005 Oct 28;4:26.

PubMed [citation]

PMID:: 16255772
PMCID:: PMC1291391

See all PubMed Citations (15)

Details of each submission

From Ambry Genetics, SCV002683966.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

The c.894G>A pathogenic mutation (also known as p.Q298Q) is located in coding exon 7 of the LIPA gene. This variant results from a G to A substitution at nucleotide position 894. This nucleotide substitution does not change the glutamine at codon 298. However, this change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. This variant is the most common mutation associated with cholesteryl ester storage disease (CESD) and haplotype analysis indicates that it is a founder mutation (Fasano T et al. Mol. Genet. Metab., 2012 Mar;105:450-6). It has been detected in the homozygous state or in trans with other pathogenic variants in numerous individuals with CESD, and it has been shown to segregate with disease in multiple families (Ameis D et al. J. Lipid Res., 1995 Feb;36:241-50; Anderson RA et al. Mol. Genet. Metab., 1999 Nov;68:333-45; Tadiboyina VT et al. Lipids Health Dis, 2005 Oct;4:26; Stitziel NO et al. Arterioscler. Thromb. Vasc. Biol., 2013 Dec;33:2909-14; Pullinger CR et al. J Clin Lipidol. 2015 Jul;9:716-26.e1; Chora JR et al. J Clin Lipidol. 2017 Nov;11:477-484.e2; Maciejko JJ et al. J Clin Lipidol. 2017 Feb;11:567-574). Functional studies have demonstrated that this alteration causes in-frame skipping of exon 7, with only ~3% of mRNA spliced correctly (Klima H et al. J. Clin. Invest., 1993 Dec;92:2713-8; Ameis D et al. J. Lipid Res., 1995 Feb;36:241-50; Aslanidis C et al. Genomics, 1996 Apr;33:85-93; Fasano T et al. Mol. Genet. Metab., 2012 Mar;105:450-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Jun 9, 2024

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