NM_000235.4(LIPA):c.894G>A (p.Gln298=) AND LIPA-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 13, 2024
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:: RCV000778291.7

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:: LIPA-related disorder
Synonyms:: LIPA-Related Disorders; LIPA-related condition
Identifiers:

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914469	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 18, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7751811, 26225414, 22227072, 10562460, 8254026, 24072694, 28502505, 25722898 Citation Link,
SCV004115067	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 13, 2024)	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

SCV000914469

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Sep 18, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV004115067

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 13, 2024)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A 5' splice-region mutation and a dinucleotide deletion in the lysosomal acid lipase gene in two patients with cholesteryl ester storage disease.

Ameis D, Brockmann G, Knoblich R, Merkel M, Ostlund RE Jr, Yang JW, Coates PM, Cortner JA, Feinman SV, Greten H.

J Lipid Res. 1995 Feb;36(2):241-50.

PubMed [citation]

PMID:: 7751811

Lysosomal Acid Lipase Deficiency.

Hoffman EP, Barr ML, Giovanni MA, Murray MF.

2015 Jul 30 [updated 2016 Sep 1]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 26225414

See all PubMed Citations (9)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914469.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Across a selection of the available literature, the LIPA c.894G>A (p.Gln298Gln) splice_region variant, (also known as E8SV or p.S275_Q298del), has been identified at least 47 individuals with cholesterol ester storage disease with variable ages of diagnoses, including at least 20 homozygotes and 27 compound heterozygotes (Klima et al. 1993; Ameis et al. 1995; Anderson et al. 1999; Fasano et al. 2012; Stitziel et al. 2013; Lin et al. 2015; Chora et al. 2017). Among individuals homozygous for the p.Gln298Gln variant, four were children or young adults clinically suspected of having familial hypercholesterolemia (FH) in whom no disease-causing variant had been identified in any FH gene (Stitziel et al. 2013; Chora et al. 2017). The p.Gln298Gln variant was also found in at least four unaffected individuals in a heterozygous state (Klima et al. 1993; Ameis et al. 1995). The p.Gln298Gln variant was absent from four control subjects and is reported at a frequency of 0.001392 in the other population of the Genome Aggregation Database. Expression analysis in patient fibroblasts found lysosomal acidic lipase (LAL) activity to be reduced to 2-16% of wild type (Klima et al. 1993; Ameis et al. 1995; Fasano et al. 2012). The p.Gln298Gln variant occurs in a canonical splice site and causes abnormal splicing resulting in an in-frame skipping of exon 8. Two transcripts are produced, one major non-functional abnormally spliced transcript missing exon 8 and one minor normally spliced transcript (3 - 5%) resulting in 5 - 10% residual LAL activity (Ameis et al. 1995; Anderson et al. 1999; Fasano et al. 2012; Hoffman et al. 2016). Transfection of the variant into COS-1 cells resulted in reduced cholesteryl esterase activity compared to controls (Anderson et al. 1999). Haplotype analysis suggests the p.Gln298Gln variant is likely to be a Mediterranean founder mutation (Fasano et al. 2012). Based on the collective evidence, the p.Gln298Gln variant is classified as pathogenic for LIPA-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 PreventionGenetics, part of Exact Sciences, SCV004115067.2

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

Description

The LIPA c.894G>A variant is not predicted to result in an amino acid change (p.=). RNA analysis has demonstrated that this variant causes exon skipping, resulting in an in-frame deletion of 72 nucleotides and a protein with 5-10% residual activity (Ameis et al. 1995. PubMed ID: 7751811; Fasano. 2012. PubMed ID: 22227072). This is the most common pathogenic variant associated with cholesteryl ester storage disease, accounting for 50-60% of disease (Bernstein et al. 2013. PubMed ID: 23485521). This variant is reported in 0.13% of alleles in individuals of European (Non-Finish) descent in gnomAD. This variant is interpreted 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

Last Updated: Jun 9, 2024

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