rs116928232

Positions:

• chr10-89222511-C-G
• chr10-89222511-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000235.4(LIPA):​c.894G>C​(p.Gln298His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000179 in 1,451,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q298Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: LIPA NM_000235.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.08

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-89222511-C-G is Pathogenic according to our data. Variant chr10-89222511-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPA	NM_000235.4	c.894G>C	p.Gln298His	missense_variant, splice_region_variant	8/10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.894G>C	p.Gln298His	missense_variant, splice_region_variant	8/10		NP_001121077.1
LIPA	NM_001288979.2	c.546G>C	p.Gln182His	missense_variant, splice_region_variant	6/8		NP_001275908.1
LIPA	XM_024448023.2	c.894G>C	p.Gln298His	missense_variant, splice_region_variant	8/10		XP_024303791.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.894G>C	p.Gln298His	missense_variant, splice_region_variant	8/10	1	NM_000235.4	ENSP00000337354	P1
LIPA	ENST00000371837.5	c.726G>C	p.Gln242His	missense_variant, splice_region_variant	7/9	2		ENSP00000360903
LIPA	ENST00000456827.5	c.546G>C	p.Gln182His	missense_variant, splice_region_variant	6/8	3		ENSP00000413019
LIPA	ENST00000428800.5			downstream_gene_variant		1		ENSP00000388415

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251194 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1451220 Hom.: 0 Cov.: 28 AF XY: 0.0000166 AC XY: 12 AN XY: 722804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lysosomal acid lipase deficiency Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jul 04, 2017	The observed mutation is not reported in 1000 genomes and ExAC databases. However, it is reported by Gomez et al. 2015. The in silico prediction of the mutation is probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The proband, born of consanguineous marriage, was presented with clinical indications of white stool, vomiting, excess crying in the night and hepatosplenomegaly from two months of age. The blood report revealed low platelet, low WBC and low hemoglobin. The proband had edema all over body. The enzyme study revealed that the proband was normal for Neiman Pick A and B disease and Gaucher disease. He died at the age of four and a half months with cardiac respiratory arrest. Mother suffered miscarriage at 1.5 months during first pregnancy. Now mother is pregnant for the third time, CVS (10 weeks) was taken to identify the same variant as found in previous child. The fetus is likely to be a carrier with Wolman disease and cholesteryl ester storage disease due to presence of heterozygous status for NM_000235.3:c.894G>C (Q298H) in exon 8 of LIPA gene. Both the parents were also studied and found to be likely carriers due to presence of the same variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The LIPA c.894G>C (p.Gln298His) variant has been reported in homozygous or compound heterozygous state in individuals affected with lysosomal acid lipase deficiency (Consuelo-Sánchez et al). The p.Gln298His variant is reported with the allele frequency of 0.001194% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic . The amino acid Gln at position 298 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gln298His in LIPA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely pathogenic. -

Wolman disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 298 of the LIPA protein (p.Gln298His). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with lysosomal acid lipase deficiency (PMID: 24048164, 28220406; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 430634). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.0	H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.8	D;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.84		Loss of MoRF binding (P = 0.1076);.;.;
MVP		0.97
MPC		0.61
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs116928232; hg19: chr10-90982268;