NM_000235.4(LIPA):c.129C>G (p.Tyr43Ter) AND Wolman disease

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jul 29, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000000102.9

Allele description [Variation Report for NM_000235.4(LIPA):c.129C>G (p.Tyr43Ter)]

NM_000235.4(LIPA):c.129C>G (p.Tyr43Ter)

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.129C>G (p.Tyr43Ter)

Other names:

Y22*

HGVS:

NC_000010.11:g.89245776G>C
NG_008194.1:g.11128C>G
NM_000235.4:c.129C>GMANE SELECT
NM_001127605.3:c.129C>G
NM_001288979.2:c.-120+5961C>G
NP_000226.2:p.Tyr43Ter
NP_001121077.1:p.Tyr43Ter
NC_000010.10:g.91005533G>C
NM_000235.3:c.129C>G

Protein change:

Y43*; TYR22TER

Links:

OMIM: 613497.0006; dbSNP: rs121965087

NCBI 1000 Genomes Browser:

rs121965087

Molecular consequence:

NM_001288979.2:c.-120+5961C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000235.4:c.129C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001127605.3:c.129C>G - nonsense - [Sequence Ontology: SO:0001587]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020245	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1996)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001406566	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 29, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23485521, 29196158, 8956047, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020245

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1996)

germline

literature only

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

SCV001406566

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 29, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

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

Prevalence of cholesteryl ester storage disease among hypercholesterolemic subjects and functional characterization of mutations in the lysosomal acid lipase gene.

Vinje T, Wierød L, Leren TP, Strøm TB.

Mol Genet Metab. 2018 Feb;123(2):169-176. doi: 10.1016/j.ymgme.2017.11.008. Epub 2017 Nov 23.

PubMed [citation]

PMID:: 29196158

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000020245.2

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

Description

In a Japanese patient with Wolman disease (WOLD; 620151), Fujiyama et al. (1996) identified a tyr22-to-ter (Y22X) mutation of the LIPA gene. The female patient had an umbilical cord herniation at birth. At about 30 days after birth, she showed abdominal distention with hepatosplenomegaly and frequent episodes of diarrhea and vomiting. Abdominal computed tomography revealed massive hepatosplenomegaly and enlargement of the adrenal glands with calcification. Anemia and hepatic failure progressed rapidly and she died at age 114 days. The parents were first cousins. An older sister had died with similar symptoms 80 days after birth.

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

From Invitae, SCV001406566.5

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

Description

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LIPA are known to be pathogenic (PMID: 23485521). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect LIPA protein function (PMID: 29196158). This variant has been observed in an individual affected with Wolman disease (PMID: 8956047). This variant is also known as p.Tyr22X in the literature. ClinVar contains an entry for this variant (Variation ID: 82). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr43*) in the LIPA gene. It is expected to result in an absent or disrupted protein product.

#	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

Last Updated: Feb 20, 2024

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