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

gnomAD frequency: 0.00075  dbSNP: rs116928232

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000478829	SCV000342914	pathogenic	not provided	2017-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000478829	SCV000568149	pathogenic	not provided	2020-08-12	criteria provided, single submitter	clinical testing	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)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000185528	SCV000743700	likely pathogenic	Lysosomal acid lipase deficiency	2017-07-28	criteria provided, single submitter	clinical testing
Invitae	RCV001376623	SCV000819258	pathogenic	Wolman disease	2024-01-31	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000185528	SCV000893853	pathogenic	Lysosomal acid lipase deficiency	2022-05-02	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000185528	SCV000898796	pathogenic	Lysosomal acid lipase deficiency	2021-03-30	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000778291	SCV000914469	pathogenic	LIPA-related disorder	2017-09-18	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000185528	SCV001193778	pathogenic	Lysosomal acid lipase deficiency	2021-11-08	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000185528	SCV001429044	pathogenic	Lysosomal acid lipase deficiency	2018-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000478829	SCV002017148	pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000185528	SCV002059314	pathogenic	Lysosomal acid lipase deficiency	2021-11-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000478829	SCV002525801	pathogenic	not provided	2021-07-14	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM2, PP3, PP4
Suma Genomics	RCV000185528	SCV002543773	pathogenic	Lysosomal acid lipase deficiency		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001376623	SCV002556229	pathogenic	Wolman disease	2022-06-29	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002372140	SCV002683966	pathogenic	Cardiovascular phenotype	2023-02-16	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV000478829	SCV003916623	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	LIPA: PP1:Strong, PS3, PP3, PP4
Payam Genetics Center, General Welfare Department of North Khorasan Province	RCV001376623	SCV003922077	pathogenic	Wolman disease	2023-03-01	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000185528	SCV003925479	likely pathogenic	Lysosomal acid lipase deficiency		criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV000778291	SCV004115067	pathogenic	LIPA-related disorder	2024-02-13	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001823874	SCV004698093	pathogenic	Cholesteryl ester storage disease	2024-02-05	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3,PP4
Neuberg Centre For Genomic Medicine, NCGM	RCV001823874	SCV005042764	pathogenic	Cholesteryl ester storage disease		criteria provided, single submitter	clinical testing	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.
OMIM	RCV001823874	SCV000020241	pathogenic	Cholesteryl ester storage disease	1996-04-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000185528	SCV000238401	pathogenic	Lysosomal acid lipase deficiency	2014-12-12	no assertion criteria provided	research	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).
GeneReviews	RCV000185528	SCV000246264	not provided	Lysosomal acid lipase deficiency		no assertion provided	literature only
Natera, Inc.	RCV000185528	SCV001453545	pathogenic	Lysosomal acid lipase deficiency	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000478829	SCV001807452	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000478829	SCV001917978	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000478829	SCV001975876	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000185528	SCV002573409	pathogenic	Lysosomal acid lipase deficiency		no assertion criteria provided	clinical testing