VCV000203361.66 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(31)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 203361 Accession: VCV000203361.66

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 89222511 (GRCh38) [ NCBI UCSC ] 10: 90982268 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 5, 2015	Oct 20, 2024	Sep 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000235.4:c.894G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000226.2:p.Gln298=	synonymous
NM_001127605.3:c.894G>A	NP_001121077.1:p.Gln298=	synonymous
NM_001288979.2:c.546G>A	NP_001275908.1:p.Gln182=	synonymous
NC_000010.11:g.89222511C>T
NC_000010.10:g.90982268C>T
NG_008194.1:g.34393G>A

... more HGVS ... less HGVS

Protein change

Other names

934G>A
E8SJ
p.Gln298=
934G-A

Canonical SPDI

NC_000010.11:89222510:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

exon loss; Variation Ontology [ VariO:0381] PubMed: 8254026

Global minor allele
frequency (GMAF)

The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (T)

Allele frequency

The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00083

Trans-Omics for Precision Medicine (TOPMed) 0.00085

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

The Genome Aggregation Database (gnomAD) 0.00075

Links

ClinGen: CA346907 OMIM: 613497.0002 dbSNP: rs116928232 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LIPA		-	-	GRCh38 GRCh37	654	686

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Lysosomal acid lipase deficiency	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	May 2, 2022	RCV000185528.37
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 1, 2023	RCV000478829.32
LIPA-related disorder	Pathogenic (2)	criteria provided, single submitter	Sep 18, 2017	RCV000778291.8
Wolman disease	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001376623.9
Cholesteryl ester storage disease	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 25, 2024	RCV001823874.8
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Feb 16, 2023	RCV002372140.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jul 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Cholesteryl ester storage disease Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743700.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Aug 22, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000342914.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 10562460‚ 22227072‚ 7751811‚ 8254026 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LIPA Number of individuals with the variant: 11 Sex: mixed
Pathogenic (Sep 18, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	LIPA-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914469.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (8) PubMed: 7751811‚ 26225414‚ 22227072‚ 10562460‚ 8254026‚ 24072694‚ 28502505‚ 25722898 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429044.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Nov 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059314.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Suma Genomics Accession: SCV002543773.1 First in ClinVar: Jul 09, 2022 Last updated: Jul 09, 2022
Pathogenic (Jun 29, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Wolman disease Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002556229.1 First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022	Publications: PubMed (6) PubMed: 31182375‚ 8617513‚ 22227072‚ 29958253‚ 31392116‚ 9684740 Comment: Variant summary: LIPA c.894G>A (p.Gln298Gln) alters a conserved nucleotide in a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered … (more) Variant summary: LIPA c.894G>A (p.Gln298Gln) alters a conserved nucleotide in a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict the variant weakens a 5' donor site. Multiple publications report experimental evidence that this variant disrupts the normal splicing sequence, resulting in alternate splicing and the skipping of exon 8 (e.g. Aslandis_1996, Pagani_1998). Although this has been shown to produce an inactive protein, the variant produces a small proportion (3-5%) of mRNA transcripts which are spliced correctly, resulting in a residual level of enzyme activity (e.g. Aslandis_1996, Pagani_1998). The variant allele was found at a frequency of 0.00091 in 251194 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.894G>A has been reported in the literature in the homozygous and compound heterozygous state in many individuals affected with Lysosomal Acid Lipase Deficiency and has been noted as one of the most common pathogenic variants associated with this disorder (e.g.Fasano_2012, Lipinski_2018, Consuelo-Sanchez_2019, Mayanskiy_2019). These data indicate that the variant is very likely to be associated with disease. Thirteen assessments for this variant have been submitted to ClinVar after 2014. Twelve submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Nov 08, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193778.4 First in ClinVar: Apr 06, 2020 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 22227072‚ 10562460‚ 21757691‚ 31182375 Comment: NM_000235.2(LIPA):c.894G>A(Q298=) is a silent variant classified as pathogenic in the context of lysosomal acid lipase deficiency. Q298= has been observed in cases with relevant disease … (more) NM_000235.2(LIPA):c.894G>A(Q298=) is a silent variant classified as pathogenic in the context of lysosomal acid lipase deficiency. Q298= has been observed in cases with relevant disease (PMID: 22227072, 31182375). Functional assessments of this variant are available in the literature (PMID: 22227072, 21757691, 10562460). Q298= has been observed in population frequency databases (gnomAD: NFE 0.13%). In summary, NM_000235.2(LIPA):c.894G>A(Q298=) is a silent variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (May 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893853.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 12, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568149.6 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate abnormal splicing resulting in an in-frame skipping of exon 8, with 3-5% of mRNA being spliced correctly (Fasano et al., 2012); … (more) Published functional studies demonstrate abnormal splicing resulting in an in-frame skipping of exon 8, with 3-5% of mRNA being spliced correctly (Fasano et al., 2012); This variant is associated with the following publications: (PMID: 8254026, 10562460, 7751811, 21757691, 26350820, 27423329, 28502505, 30249571, 32093730, 22227072, 19307143, 23424026, 25722898, 22795295, 24072694, 16255772, 29884776, 25852113, 30548430, 30684275, 28502515, 29982809, 30056760, 29958253, 32382506, 31980526, 34426522, 33857477, 31589614, 33108087, 33269076, 7759067, 32432142, 32531373) (less)
Pathogenic (Mar 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV000898796.2 First in ClinVar: Apr 26, 2019 Last updated: May 06, 2023	Comment: LIPA NM_000235.3 exon 8 p.Gln298= (c.894G>A): This variant has been reported in the literature in several individuals with Lysosomal Acid Lipase Deficiency and is one … (more) LIPA NM_000235.3 exon 8 p.Gln298= (c.894G>A): This variant has been reported in the literature in several individuals with Lysosomal Acid Lipase Deficiency and is one of the most common pathogenic variants for this gene, including a GeneReviews entry (Pisciotta 2009 PMID:19307143, Fasano 2012 PMID:22227072, Bernstein 2013 PMID:23485521, Hoffman 2016 PMID:26225414). This variant is present in 0.1% (164/126436) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs116928232). This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:203361). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid; however, functional studies suggest that this variant disrupts the normal splicing sequence, resulting in the alternate splicing and skipping of exon 8 (Pisciotta 2009 PMID:19307143, Fasano 2012 PMID:22227072, Bernstein 2013 PMID:23485521, Hoffman 2016 PMID:26225414). In summary, this variant is classified as pathogenic. (less)
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017148.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Wolman disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000819258.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 28492532‚ 22227072‚ 23424026‚ 23485521‚ 7759067‚ 8617513‚ 9684740‚ 17576681‚ 9536098‚ 8254026 Comment: This sequence change affects codon 298 of the LIPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 298 of the LIPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LIPA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs116928232, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with cholesteryl ester storage disease and is estimated to be carried by 40-60% of affected individuals (PMID: 22227072, 23424026, 23485521). ClinVar contains an entry for this variant (Variation ID: 203361). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LIPA function (PMID: 7759067, 8617513, 9684740). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 8254026). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002525801.2 First in ClinVar: Jun 11, 2022 Last updated: Jun 09, 2024	Publications: Bookshelf: NBK305870 Bookshelf: NBK305870 Comment: PS3, PS4_moderate, PM2, PP3, PP4 Number of individuals with the variant: 5
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wolman disease Affected status: no Allele origin: germline	Payam Genetics Center, General Welfare Department of North Khorasan Province Accession: SCV003922077.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Number of individuals with the variant: 1 Age: 10-19 years Sex: male Ethnicity/Population group: Iranian Geographic origin: Iran
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003925479.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Publications: PubMed (1) PubMed: 22227072 Comment: A Heterozygous Synonymous variant c.894G>A in Exon 8 of the LIPA gene that results in the amino acid substitution p.Gln298Gln was identified. The observed variant … (more) A Heterozygous Synonymous variant c.894G>A in Exon 8 of the LIPA gene that results in the amino acid substitution p.Gln298Gln was identified. The observed variant has a maximum allele frequency of 0.00091/0.00083% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is diseasecausing. ClinVar has also classified this variant as Pathogenic/ LikelyPathogenic (Variant ID: 203361). This variant was reported among patients for Wolman Disease and cholesteryl ester storage disease. (Fasano T et al, 2012). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004698093.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Comment: Criteria applied: PM3_VSTR,PS3,PP4 Clinical Features: Increased LDL cholesterol concentration (present) , Hypercholesterolemia (present) Sex: female
Pathogenic (Feb 16, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002683966.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (15) PubMed: 10562460‚ 16255772‚ 21757691‚ 22227072‚ 22795295‚ 23424026‚ 24072694‚ 25722898‚ 25852113‚ 26350820‚ 28502505‚ 28502515‚ 7751811‚ 8254026‚ 8617513 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005042764.1 First in ClinVar: May 12, 2024 Last updated: May 12, 2024	Comment: The splice region and synonymous c.894G>Ap.Gln298 variant in LIPA gene has been reported previously in homozygous state in individuals affected with cholesteryl ester storage disease … (more) The splice region and synonymous c.894G>Ap.Gln298 variant in LIPA gene has been reported previously in homozygous state in individuals affected with cholesteryl ester storage disease and is estimated to be carried by 40-60% of affected individuals Bernstein et al., 2013. Experimental studies have shown that this variant affects LIPA function Pagani et al., 1998. This variant is reported with the allele frequency of 0.09% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. This variant creates a cryptic splice donor site within exon 8 and causes abnormal gene splicing. The spliceAI tool predicts that this splice site variant is damaging. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cholesteryl ester storage disease Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051850.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Sep 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cholesteryl ester storage disease Affected status: yes Allele origin: unknown	KardioGenetik, Herz- und Diabeteszentrum NRW Accession: SCV005373793.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 Comment: heterozygous state, elevated ALT activity, PVS1_strong, PS3_supporting, PP1_strong	Number of individuals with the variant: 1
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916623.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: LIPA: PP1:Strong, PS3, PP3, PP4 Number of individuals with the variant: 2
Pathogenic (Dec 12, 2014)	no assertion criteria provided Method: research	Cholesteryl ester storage disease Affected status: no Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000238401.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Publications: PubMed (2) PubMed: 8254026‚ 22227072 Comment: This patient is a carrier of a heterozygous pathogenic variant in the LIPA gene associated with cholesterol ester storage disease (MIM 278000). This is a … (more) This patient is a carrier of a heterozygous pathogenic variant in the LIPA gene associated with cholesterol ester storage disease (MIM 278000). This is a well documented pathogenic variant (Kilma et al. 1993, PMID: 8254026; Fasano et al. 2012, PMID: 22227072) in the last base of exon 8 (canonical splice site). The variant has been shown to result in a major non-functional transcript (with skipping of exon 8), and a minor normally spliced protein with 5-10% residual enzyme activity (Kilma et al. 1993, PMID: 8254026; Fasano et al. 2012, PMID: 22227072). (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Lysosomal acid lipase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453545.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807452.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917978.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975876.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Apr 01, 1996)	no assertion criteria provided Method: literature only	CHOLESTERYL ESTER STORAGE DISEASE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020241.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 10, 2023	Publications: PubMed (4) PubMed: 8254026‚ 8617513‚ 8598644‚ 7759067 Maslen, C. L., Illingworth, D. R. (more...) Maslen, C. L., Illingworth, D. R. Molecular genetics of cholesterol ester hydrolase deficiency. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A926, 1993. Comment on evidence: In a 12-year-old patient with cholesteryl ester storage disease (CESD; 278000) from a nonconsanguineous Polish-German family, Klima et al. (1993) detected a 72-bp in-frame deletion … (more) In a 12-year-old patient with cholesteryl ester storage disease (CESD; 278000) from a nonconsanguineous Polish-German family, Klima et al. (1993) detected a 72-bp in-frame deletion resulting in the loss of amino acid codons 254 through 277. Analysis of genomic DNA revealed that the 72 bp represented an exon, indicating that the deletion in the mRNA was caused by defective splicing. Sequence analysis of the patient's genomic DNA revealed a G-to-A substitution in the last nucleotide of the 72-bp exon on 1 allele. No normal-sized mRNA was detectable in the propositus even though he was not homozygous for the splice site mutation. Klima et al. (1993) concluded that the patient was compound heterozygous for the splice site mutation and a null allele. The patient showed LIPA activity in cultured skin fibroblasts approximately 9% of normal. Hepatosplenomegaly had been present since age 5 years. Aslanidis et al. (1996) restudied the patient of Klima et al. (1993) and defined the splice site mutation as a G-to-A mutation at position -1 of the splice donor site following exon 8, resulting in incorrect splicing and the removal of the 72-bp exon 8 of the LIPA gene. They determined that the other allele of the patient carried a premature termination mutation (613497.0003) as well as the L179P mutation (613497.0001); the LIPA mRNA was rendered unstable by the premature stop codon. Aslanidis et al. (1996) demonstrated that the splice site mutation allowed the production of approximately 3 to 4% of correctly spliced mRNA relative to wildtype. Aslanidis et al. (1996) also identified a mutation at the same splice donor site, and also resulting in deletion of exon 8, in 2 sibs with Wolman disease; that mutation, at the +1 position, allowed no correct splicing, and patient fibroblasts were devoid of enzymatic activity. See 613497.0005. In 2 sibs with CESD, Maslen and Illingworth (1993) and Maslen et al. (1995) identified compound heterozygosity for this splice site mutation in the LIPA gene, inherited from their father, and the L179P mutation (613497.0001). The affected children were a sister and brother who presented with idiopathic hepatomegaly at ages 6 and 8 years, respectively. Subsequent analyses indicated that they also had hypercholesterolemia and a severe reduction in cholesteryl ester hydrolase activity in cultured fibroblasts. Muntoni et al. (1995) observed homozygosity for the splice site mutation (Klima et al., 1993) in a Spanish kindred with cholesterol ester storage disease. Exon 8 of the LIPA gene was deleted. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Cholesteryl ester storage disease Affected status: unknown Allele origin: germline	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" Accession: SCV002573409.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022
Pathogenic (Feb 13, 2024)	no assertion criteria provided Method: clinical testing	LIPA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115067.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The LIPA c.894G>A is a noncoding alteration. RNA analysis has demonstrated that this variant causes exon skipping, resulting in an in-frame deletion of 72 nucleotides … (more) The LIPA c.894G>A is a noncoding alteration. 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. (less)
not provided (-)	no classification provided Method: literature only	Lysosomal acid lipase deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000246264.3 First in ClinVar: Oct 01, 2015 Last updated: Oct 01, 2022 Comment: At splice donor site of exon 8, resulting in alternative splicing and subsequent skipping of exon 8.	Publications: PubMed (3) PubMed: 23485521‚ 24072694‚ 23424026 BookShelf: NBK305870 BookShelf: NBK305870
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Comment:

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.

Comment:

Variant summary: LIPA c.894G>A (p.Gln298Gln) alters a conserved nucleotide in a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict the variant weakens a 5' donor site. Multiple publications report experimental evidence that this variant disrupts the normal splicing sequence, resulting in alternate splicing and the skipping of exon 8 (e.g. Aslandis_1996, Pagani_1998). Although this has been shown to produce an inactive protein, the variant produces a small proportion (3-5%) of mRNA transcripts which are spliced correctly, resulting in a residual level of enzyme activity (e.g. Aslandis_1996, Pagani_1998). The variant allele was found at a frequency of 0.00091 in 251194 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.894G>A has been reported in the literature in the homozygous and compound heterozygous state in many individuals affected with Lysosomal Acid Lipase Deficiency and has been noted as one of the most common pathogenic variants associated with this disorder (e.g.Fasano_2012, Lipinski_2018, Consuelo-Sanchez_2019, Mayanskiy_2019). These data indicate that the variant is very likely to be associated with disease. Thirteen assessments for this variant have been submitted to ClinVar after 2014. Twelve submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NM_000235.2(LIPA):c.894G>A(Q298=) is a silent variant classified as pathogenic in the context of lysosomal acid lipase deficiency. Q298= has been observed in cases with relevant disease (PMID: 22227072, 31182375). Functional assessments of this variant are available in the literature (PMID: 22227072, 21757691, 10562460). Q298= has been observed in population frequency databases (gnomAD: NFE 0.13%). In summary, NM_000235.2(LIPA):c.894G>A(Q298=) is a silent variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Published functional studies demonstrate abnormal splicing resulting in an in-frame skipping of exon 8, with 3-5% of mRNA being spliced correctly (Fasano et al., 2012); This variant is associated with the following publications: (PMID: 8254026, 10562460, 7751811, 21757691, 26350820, 27423329, 28502505, 30249571, 32093730, 22227072, 19307143, 23424026, 25722898, 22795295, 24072694, 16255772, 29884776, 25852113, 30548430, 30684275, 28502515, 29982809, 30056760, 29958253, 32382506, 31980526, 34426522, 33857477, 31589614, 33108087, 33269076, 7759067, 32432142, 32531373)

Comment:

LIPA NM_000235.3 exon 8 p.Gln298= (c.894G>A): This variant has been reported in the literature in several individuals with Lysosomal Acid Lipase Deficiency and is one of the most common pathogenic variants for this gene, including a GeneReviews entry (Pisciotta 2009 PMID:19307143, Fasano 2012 PMID:22227072, Bernstein 2013 PMID:23485521, Hoffman 2016 PMID:26225414). This variant is present in 0.1% (164/126436) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs116928232). This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:203361). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid; however, functional studies suggest that this variant disrupts the normal splicing sequence, resulting in the alternate splicing and skipping of exon 8 (Pisciotta 2009 PMID:19307143, Fasano 2012 PMID:22227072, Bernstein 2013 PMID:23485521, Hoffman 2016 PMID:26225414). In summary, this variant is classified as pathogenic.

Comment:

This sequence change affects codon 298 of the LIPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LIPA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs116928232, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with cholesteryl ester storage disease and is estimated to be carried by 40-60% of affected individuals (PMID: 22227072, 23424026, 23485521). ClinVar contains an entry for this variant (Variation ID: 203361). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects LIPA function (PMID: 7759067, 8617513, 9684740). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 8254026). For these reasons, this variant has been classified as Pathogenic.

Comment:

A Heterozygous Synonymous variant c.894G>A in Exon 8 of the LIPA gene that results in the amino acid substitution p.Gln298Gln was identified. The observed variant has a maximum allele frequency of 0.00091/0.00083% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is diseasecausing. ClinVar has also classified this variant as Pathogenic/ LikelyPathogenic (Variant ID: 203361). This variant was reported among patients for Wolman Disease and cholesteryl ester storage disease. (Fasano T et al, 2012). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

Comment:

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.

Comment:

The splice region and synonymous c.894G>Ap.Gln298 variant in LIPA gene has been reported previously in homozygous state in individuals affected with cholesteryl ester storage disease and is estimated to be carried by 40-60% of affected individuals Bernstein et al., 2013. Experimental studies have shown that this variant affects LIPA function Pagani et al., 1998. This variant is reported with the allele frequency of 0.09% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. This variant creates a cryptic splice donor site within exon 8 and causes abnormal gene splicing. The spliceAI tool predicts that this splice site variant is damaging. For these reasons, this variant has been classified as Pathogenic.

Comment:

This patient is a carrier of a heterozygous pathogenic variant in the LIPA gene associated with cholesterol ester storage disease (MIM 278000). This is a well documented pathogenic variant (Kilma et al. 1993, PMID: 8254026; Fasano et al. 2012, PMID: 22227072) in the last base of exon 8 (canonical splice site). The variant has been shown to result in a major non-functional transcript (with skipping of exon 8), and a minor normally spliced protein with 5-10% residual enzyme activity (Kilma et al. 1993, PMID: 8254026; Fasano et al. 2012, PMID: 22227072).

Comment:

The LIPA c.894G>A is a noncoding alteration. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A kinetic assay of total lipase activity for detecting lysosomal acid lipase deficiency (LAL-D) and the molecular characterization of 18 LAL-D patients from Russia.	Mayanskiy N	JIMD reports	2019	PMID: 31392116
Mutations identified in a cohort of Mexican patients with lysosomal acid lipase deficiency.	Consuelo-Sánchez A	Annals of hepatology	2019	PMID: 31182375
Diagnostic Algorithm for Cholesteryl Ester Storage Disease: Clinical Presentation in 19 Polish Patients.	Lipiński P	Journal of pediatric gastroenterology and nutrition	2018	PMID: 29958253
Lysosomal acid lipase deficiency in all siblings of the same parents.	Maciejko JJ	Journal of clinical lipidology	2017	PMID: 28502515
Lysosomal acid lipase deficiency: A hidden disease among cohorts of familial hypercholesterolemia?	Chora JR	Journal of clinical lipidology	2017	PMID: 28502505
Lysosomal Acid Lipase Deficiency.	Adam MP	-	2016	PMID: 26225414
Identification and metabolic profiling of patients with lysosomal acid lipase deficiency.	Pullinger CR	Journal of clinical lipidology	2015	PMID: 26350820
Hypercholesterolaemia and hepatosplenomegaly: two manifestations of cholesteryl ester storage disease.	Sjouke B	The Netherlands journal of medicine	2015	PMID: 25852113
Novel mutation in a patient with cholesterol ester storage disease.	Lin P	Case reports in genetics	2015	PMID: 25722898
Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia.	Stitziel NO	Arteriosclerosis, thrombosis, and vascular biology	2013	PMID: 24072694
Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease.	Bernstein DL	Journal of hepatology	2013	PMID: 23485521
Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups.	Scott SA	Hepatology (Baltimore, Md.)	2013	PMID: 23424026
Heterozygosity for lysosomal acid lipase E8SJM mutation and serum lipid concentrations.	Muntoni S	Nutrition, metabolism, and cardiovascular diseases : NMCD	2013	PMID: 22795295
Lysosomal lipase deficiency: molecular characterization of eleven patients with Wolman or cholesteryl ester storage disease.	Fasano T	Molecular genetics and metabolism	2012	PMID: 22227072
Lysosomal acid lipase deficiency impairs regulation of ABCA1 gene and formation of high density lipoproteins in cholesteryl ester storage disease.	Bowden KL	The Journal of biological chemistry	2011	PMID: 21757691
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease.	Tadiboyina VT	Lipids in health and disease	2005	PMID: 16255772
Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease.	Anderson RA	Molecular genetics and metabolism	1999	PMID: 10562460
New lysosomal acid lipase gene mutants explain the phenotype of Wolman disease and cholesteryl ester storage disease.	Pagani F	Journal of lipid research	1998	PMID: 9684740
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
Genetic and biochemical evidence that CESD and Wolman disease are distinguished by residual lysosomal acid lipase activity.	Aslanidis C	Genomics	1996	PMID: 8617513
Occurrence of a mutation associated with Wolman disease in a family with cholesteryl ester storage disease.	Maslen CL	Journal of inherited metabolic disease	1995	PMID: 8598644
Homozygosity for a splice junction mutation in exon 8 of the gene encoding lysosomal acid lipase in a Spanish kindred with cholesterol ester storage disease (CESD).	Muntoni S	Human genetics	1995	PMID: 7759067
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	Journal of lipid research	1995	PMID: 7751811
A splice junction mutation causes deletion of a 72-base exon from the mRNA for lysosomal acid lipase in a patient with cholesteryl ester storage disease.	Klima H	The Journal of clinical investigation	1993	PMID: 8254026
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LIPA	-	-	-	-
Maslen, C. L., Illingworth, D. R. Molecular genetics of cholesterol ester hydrolase deficiency. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A926, 1993.	-	-	-	-
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Text-mined citations for rs116928232 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs116928232 ...