10-89222511-C-T

Position:

• chr10-89222511-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000235.4(LIPA):​c.894G>A​(p.Gln298Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00111 in 1,603,504 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: LIPA NM_000235.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:31 O:1
• Conservation: PhyloP100: 7.08

Genes affected

LIPA (HGNC:6617): (lipase A, lysosomal acid type) This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 10-89222511-C-T is Pathogenic according to our data. Variant chr10-89222511-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89222511-C-T is described in Lovd as [Pathogenic]. Variant chr10-89222511-C-T is described in Lovd as [Likely_pathogenic]. Variant chr10-89222511-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPA	NM_000235.4	c.894G>A	p.Gln298Gln	splice_region_variant, synonymous_variant	8/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.894G>A	p.Gln298Gln	splice_region_variant, synonymous_variant	8/10		NP_001121077.1
LIPA	NM_001288979.2	c.546G>A	p.Gln182Gln	splice_region_variant, synonymous_variant	6/8		NP_001275908.1
LIPA	XM_024448023.2	c.894G>A	p.Gln298Gln	splice_region_variant, synonymous_variant	8/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.894G>A	p.Gln298Gln	splice_region_variant, synonymous_variant	8/10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000371837.5	c.726G>A	p.Gln242Gln	splice_region_variant, synonymous_variant	7/9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.546G>A	p.Gln182Gln	splice_region_variant, synonymous_variant	6/8	3		ENSP00000413019.2
LIPA	ENST00000428800.5	c.*22G>A		downstream_gene_variant		1		ENSP00000388415.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000908 AC: 228 AN: 251194 Hom.: 0 AF XY: 0.000921 AC XY: 125 AN XY: 135766

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00115 AC: 1666 AN: 1451190 Hom.: 2 Cov.: 28 AF XY: 0.00115 AC XY: 832 AN XY: 722786

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.000576

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000546

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74470

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000737

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:31 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysosomal acid lipase deficiency Pathogenic:11 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Nov 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	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. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Dec 12, 2014	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). -
Pathogenic, criteria provided, single submitter	clinical testing	GENinCode PLC	Jan 07, 2025	The c.894G>A p.(Gln298=) variant in LIPA has been reported in the homozygous and compound heterozygous state in numerous patients with a clinical diagnosis of Lysosomal acid lipase deficiency (PM3_VERY STRONG, PP4_SUPPORTING; PMIDs 7751811, 7759067, 8254026, 8598644, 8617513, 9684740, 10562460, 22227072, 23424026, 23485521, 24072694, 25722898, 28502505, 28220406, 29958253, 31182375, 31392116, 32058863, internal data). This variant has also been shown to segregate with disease in multiple families (PP1_STRONG; PMIDs 24072694, 28502505, 31182375, 31392116, internal data). Functional studies have demonstrated that this variant leads to skipping of exon 8 in 95% of mRNA transcripts and the recombinant mutant protein lacks functional activity (PS3_STRONG; PMIDs 7751811, 9684740). Based on the evidence listed above, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	LIPA: PP1:Strong, PS3, PP3, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2020	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 01, 2024	- -

Cholesteryl ester storage disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	KardioGenetik, Herz- und Diabeteszentrum NRW	Sep 25, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 05, 2024	Criteria applied: PM3_VSTR,PS3,PP4 -

Wolman disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 29, 2022	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. -

LIPA-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 13, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 2017	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. -

Cholesteryl ester storage disease;C0043208:Wolman disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2024

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs116928232; hg19: chr10-90982268;