ClinVar Miner

Submissions for variant NM_000235.4(LIPA):c.894G>A (p.Gln298=) (rs116928232)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000478829 SCV000342914 pathogenic not provided 2017-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000478829 SCV000568149 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The c.894G>A pathogenic variant in the LIPA gene has been reported previously as a common variant associated with cholesteryl ester storage disease when present in the homozygous state or when in trans with another pathogenic variant (Fasano et al., 2012). Studies showed that this variant causes abnormal splicing resulting in an in-frame skipping of exon 8, with 3-5% of mRNA being spliced correctly. Residual protein activity of 2-12% was seen in lymphocytes or fibroblasts of affected individuals compared to controls (Fasano et al., 2012). In summary, we interpret c.894G>A as a pathogenic variant.
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 2020-10-20 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. This variant also falls at the last nucleotide of exon 8 of the LIPA coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs116928232, ExAC 0.1%). This variant has been observed in multiple individuals affected with cholesteryl ester storage disease and is estimated to be carried by 40-60% of affected individuals (PMID: 22227072, 23485521, 23424026). ClinVar contains an entry for this variant (Variation ID: 203361). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this splice variant change produces an altered transcript with 5-10% residual activity (PMID: 8617513, 8254026, 7759067, 9684740). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000185528 SCV000893853 pathogenic Lysosomal acid lipase deficiency 2018-10-31 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 2018-05-18 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 Clinical Services Laboratory,Illumina RCV000778291 SCV000914469 pathogenic LIPA-Related Disorders 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 Women's Health, Inc. RCV000185528 SCV001193778 likely pathogenic Lysosomal acid lipase deficiency 2019-12-20 criteria provided, single submitter clinical testing NM_000235.2(LIPA):c.894G>A(aka Q298=) is classified as likely pathogenic in the context of lysosomal acid lipase deficiency and may be associated with cholesteryl ester storage disease. Sources cited for classification include the following: PMID 22227072, 10562460 and 21757691. Classification of NM_000235.2(LIPA):c.894G>A(aka Q298=) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses 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
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 pathogenic Lysosomal acid lipase deficiency 2016-09-01 no assertion criteria provided literature only
Natera, Inc. RCV000185528 SCV001453545 pathogenic Lysosomal acid lipase deficiency 2020-09-16 no assertion criteria provided clinical testing

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