10-89228375-G-T

Variant names:

• chr10-89228375-G-T
• rs797045094
• NM_000235.4:c.253C>A

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.253C>A​(p.Gln85Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.73

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: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 10-89228375-G-T is Pathogenic according to our data. Variant chr10-89228375-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 695063.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	c.253C>A	p.Gln85Lys	missense_variant	Exon 4 of 10	ENST00000336233.10	NP_000226.2
LIPA	NM_001127605.3	c.253C>A	p.Gln85Lys	missense_variant	Exon 4 of 10		NP_001121077.1
LIPA	XM_024448023.2	c.253C>A	p.Gln85Lys	missense_variant	Exon 4 of 10		XP_024303791.1
LIPA	NM_001288979.2	c.-96C>A		5_prime_UTR_variant	Exon 2 of 8		NP_001275908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.253C>A	p.Gln85Lys	missense_variant	Exon 4 of 10	1	NM_000235.4	ENSP00000337354.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wolman disease Pathogenic:2

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 85 of the LIPA protein (p.Gln85Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with lysosomal acid lipase deficiency (PMID: 25624737, 31182375; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 695063). 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. Experimental studies have shown that this missense change affects LIPA function (PMID: 29196158, 31131398, 31180157). This variant disrupts the p.Gln85 amino acid residue in LIPA. Other variant(s) that disrupt this residue have been observed in individuals with LIPA-related conditions (PMID: 9684740), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Mar 02, 2022

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.253C>A (p.Gln85Lys) results in a conservative amino acid change located in the Alpha/beta hydrolase fold-1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.253C>A has been reported in the literature in individuals affected with Lysosomal Acid Lipase Deficiency in the homozygous and compound heterozygous state (Consuelo-Sanchez_2019, Cappuccio_2019). These data indicate that the variant is likely to be associated with disease. A functional study reports the variant the result in <10% enzyme activity in transiently transfected cell lysates (Vinje_2018). In addition, a different variant affecting the same codon (Q85R) has been reported in association with cholesterol ester storage disease (HGMD). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lysosomal acid lipase deficiency Pathogenic:1

Jun 01, 2019

Alexion, Astrazeneca Rare Disease, Astrazeneca

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Cholesteryl ester storage disease Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.253C>Ap.Gln85Lys variant in LIPA gene has been reported in compound heterozygous/ homozygous state in individuals affected with LIPA associated disorder Cappuccio G, et. al., 2019; Consuelo-Sánchez A, et. al., 2019; Del Angel G, et.al., 2019. Experimental studies have shown that this missense change affects LIPA function Pagani F, et.al., 1998. This variant is present with an allele frequency of 0.0004% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely pathogenic/ Pathogenic. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease Causing predict damaging effect on protein structure and function for this variant. The reference amino acid in LIPA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 85 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.;T
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.5	H;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.030	D;D;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.95
MutPred		0.88		Gain of ubiquitination at Q85 (P = 0.0388);.;Gain of ubiquitination at Q85 (P = 0.0388);Gain of ubiquitination at Q85 (P = 0.0388);
MVP		0.94
MPC		0.71
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs797045094; hg19: chr10-90988132;