NM_000235.4(LIPA):c.894G>A (p.Gln298=) AND Lysosomal acid lipase deficiency

Germline classification:: Pathogenic/Likely pathogenic (12 submissions)
Last evaluated:: May 2, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000185528.35

Allele description [Variation Report for NM_000235.4(LIPA):c.894G>A (p.Gln298=)]

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

Gene:

LIPA:lipase A, lysosomal acid type [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

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

Other names:

934G>A; E8SJ; p.Gln298=

HGVS:

NC_000010.11:g.89222511C>T
NG_008194.1:g.34393G>A
NM_000235.4:c.894G>AMANE SELECT
NM_001127605.3:c.894G>A
NM_001288979.2:c.546G>A
NP_000226.2:p.Gln298=
NP_001121077.1:p.Gln298=
NP_001275908.1:p.Gln182=
NC_000010.10:g.90982268C>T
NM_000235.2:c.894G>A
NM_000235.3:c.894G>A
NM_001127605.1:c.894G>A
NP_001121077.1:p.=

Nucleotide change:

934G-A

Links:

OMIM: 613497.0002; dbSNP: rs116928232

NCBI 1000 Genomes Browser:

rs116928232

Molecular consequence:

NM_000235.4:c.894G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001127605.3:c.894G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001288979.2:c.546G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

exon loss [PubMedVariation Ontology: 0381]

Observations:

Condition(s)

Name:: Lysosomal acid lipase deficiency
Synonyms:: Acid cholesteryl ester hydrolase deficiency, type 2
Identifiers:: MONDO: MONDO:0800449; MedGen: C2936797; OMIM: PS278000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000238401	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Pathogenic (Dec 12, 2014)	germline	research	PubMed (2) [See all records that cite these PMIDs] 8254026, 22227072
SCV000246264	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 23485521, 24072694, 23424026
SCV000743700	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Jul 28, 2017)	germline	clinical testing	Citation Link,
SCV000893853	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000898796	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193778	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Nov 8, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22227072, 10562460, 21757691, 31182375 Citation Link,
SCV001429044	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453545	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002059314	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002543773	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002573409	Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV003925479	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22227072, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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, Ullrich K, Aslanidis C, Fehringer P, Lackner KJ, Schmitz G.

J Clin Invest. 1993 Dec;92(6):2713-8.

PubMed [citation]

PMID:: 8254026
PMCID:: PMC288469

Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease.

Bernstein DL, Hülkova H, Bialer MG, Desnick RJ.

J Hepatol. 2013 Jun;58(6):1230-43. doi: 10.1016/j.jhep.2013.02.014. Epub 2013 Feb 26. Review.

PubMed [citation]

PMID:: 23485521

See all PubMed Citations (9)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000238401.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000246264.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV000743700.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893853.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898796.2

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

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193778.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429044.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Natera, Inc., SCV001453545.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059314.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Suma Genomics, SCV002543773.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska", SCV002573409.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Lifecell International Pvt. Ltd, SCV003925479.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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