rs121965086

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_000235.4(LIPA):c.599T>C(p.Leu200Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L200L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

LIPA
NM_000235.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.07

Publications

8 publications found

Variant links:

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]

LIPA Gene-Disease associations (from GenCC):

lysosomal acid lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
cholesteryl ester storage disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Wolman disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LIPA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 39 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.22832 (below the threshold of 3.09). Trascript score misZ: 0.63421 (below the threshold of 3.09). GenCC associations: The gene is linked to cholesteryl ester storage disease, lysosomal acid lipase deficiency, Wolman disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 10-89225168-A-G is Pathogenic according to our data. Variant chr10-89225168-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 77.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4 link	c.599T>C	p.Leu200Pro	missense_variant	Exon 6 of 10	ENST00000336233.10	NP_000226.2	P38571-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10 link	c.599T>C	p.Leu200Pro	missense_variant	Exon 6 of 10	1	NM_000235.4	ENSP00000337354.5		P38571-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251462

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111978

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000493

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wolman disease

Pathogenic:3

Jul 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LIPA protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LIPA function (PMID: 7499245, 10562460). ClinVar contains an entry for this variant (Variation ID: 77). This variant is also known as L179P. This missense change has been observed in individual(s) with cholesterol ester storage disease (CESD) or Wolman disease (PMID: 8146180, 8598644, 8617513, 23430518). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121965086, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the LIPA protein (p.Leu200Pro). -

Feb 16, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LIPA c.599T>C (p.Leu200Pro) results in a non-conservative amino acid change located in the Alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. This variant is also known as L179P. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251462 control chromosomes (gnomAD). c.599T>C has been reported in the literature in individuals affected with Lysosomal Acid Lipase Deficiency (examples: Pullinger_2015, Ambler_2012, Anderson_1994, Maslen_1995). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Vinje_2019) . Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lysosomal acid lipase deficiency

Pathogenic:3

Jan 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jul 07, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 16, 2023

GENinCode PLC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.599T>C p.(Leu200Pro) variant in LIPA is a missense variant that has been seen in several patients with a clinical diagnosis of Lysosomal Acid Lipase Deficiency who also carry a second pathogenic LIPA variant (PM3_STRONG, PP4_SUPPORTING; PMIDs 8146180, 8598644, 23430518, 26350820). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002458 in European (non-Finnish) population (PM2_MODERATE). Functional studies demonstrated loss of enzyme activity in vitro (PS3_STRONG; PMIDs 7499245, 8146180, 31131398, 31180157) and the REVEL score is 0.896 (PP3_SUPPORTING). Based on the evidence listed above, this variant has been classified as pathogenic. -

Cholesteryl ester storage disease

Pathogenic:1

Aug 08, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;.;T;.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Pathogenic

4.5

H;.;.;.;.

PhyloP100

8.1

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-6.7

D;D;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.96

MutPred

0.97

Loss of stability (P = 0.0102);.;.;Loss of stability (P = 0.0102);Loss of stability (P = 0.0102);

MVP

0.99

MPC

0.80

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over