10-89215004-C-G

Variant names:

• chr10-89215004-C-G
• rs776472526
• NM_000235.4:c.1024G>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000235.4(LIPA):​c.1024G>C​(p.Gly342Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G342W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.99
• Publications: 0 publications found

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

ACMG classification

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

• PS1: Transcript NM_000235.4 (LIPA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-89215004-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 695041.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.993
• PP5: Variant 10-89215004-C-G is Pathogenic according to our data. Variant chr10-89215004-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1350454.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.1024G>C	p.Gly342Arg	missense_variant	Exon 10 of 10	ENST00000336233.10	NP_000226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.1024G>C	p.Gly342Arg	missense_variant	Exon 10 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000371837.5	c.856G>C	p.Gly286Arg	missense_variant	Exon 9 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.676G>C	p.Gly226Arg	missense_variant	Exon 8 of 8	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Wolman disease Pathogenic:1

Mar 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with arginine at codon 342 of the LIPA protein (p.Gly342Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). A different variant (c.1024G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 10562460, 28881270, 24048164, 23485521). This suggests that this variant is also likely to be causative of disease. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.5	H;.;.
PhyloP100		7.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.5	D;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.98		Loss of glycosylation at S341 (P = 0.0508);.;.;
MVP		0.96
MPC		0.68
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs776472526; hg19: chr10-90974761;