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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV001376623.9

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:: Wolman disease (WOLD)
Synonyms:: Acid cholesteryl ester hydrolase deficiency, Wolman type; Acid lipase disease; Wolman disease, CESD; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0019148; MedGen: C0043208; OMIM: 620151

Recent activity

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MULTISPECIES: YmjA family protein [Bacteria]
MULTISPECIES: YmjA family protein [Bacteria]
gi|490284235|ref|WP_004180069.1|

Protein
Fistularia commersonii voucher EIL060506 D-loop, partial sequence; mitochondrial
Fistularia commersonii voucher EIL060506 D-loop, partial sequence; mitochondrial
gi|756766354|gb|KP053057.1|

Nucleotide
phosphatidylinositol 4-kinase beta isoform X1 [Homo sapiens]
phosphatidylinositol 4-kinase beta isoform X1 [Homo sapiens]
gi|767909543|ref|XP_011507936.1|

Protein
U5 small nuclear ribonucleoprotein TSSC4 isoform X1 [Danio rerio]
U5 small nuclear ribonucleoprotein TSSC4 isoform X1 [Danio rerio]
gi|528485143|ref|XP_005168945.1|

Protein
RecName: Full=Conotoxin LeD51; Flags: Precursor
RecName: Full=Conotoxin LeD51; Flags: Precursor
gi|122011887|sp|Q3YEF7.1|O2651_CONL

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000819258	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 22227072, 23424026, 23485521, 7759067, 8617513, 9684740, 17576681, 9536098, 8254026, 28492532
SCV002556229	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 29, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 31182375, 8617513, 22227072, 29958253, 31392116, 9684740 Citation Link,
SCV003922077	Payam Genetics Center, General Welfare Department of North Khorasan Province	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000819258

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002556229

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 29, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV003922077

Payam Genetics Center, General Welfare Department of North Khorasan Province

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 1, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Iranian	germline	no	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups.

Scott SA, Liu B, Nazarenko I, Martis S, Kozlitina J, Yang Y, Ramirez C, Kasai Y, Hyatt T, Peter I, Desnick RJ.

Hepatology. 2013 Sep;58(3):958-65. doi: 10.1002/hep.26327. Epub 2013 Jul 29.

PubMed [citation]

PMID:: 23424026
PMCID:: PMC3690149

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 (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000819258.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002556229.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	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 Payam Genetics Center, General Welfare Department of North Khorasan Province, SCV003922077.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Iranian	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	no	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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