10-89223710-C-T

Variant names:

• chr10-89223710-C-T
• rs267607218
• NM_000235.4:c.796G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_000235.4(LIPA):​c.796G>A​(p.Gly266Arg) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G266G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LIPA NM_000235.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.33
• 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: Likely_pathogenic. The variant received 7 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, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPA	NM_000235.4	c.796G>A	p.Gly266Arg	missense_variant	Exon 7 of 10	ENST00000336233.10	NP_000226.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPA	ENST00000336233.10	c.796G>A	p.Gly266Arg	missense_variant	Exon 7 of 10	1	NM_000235.4	ENSP00000337354.5
LIPA	ENST00000428800.5	c.796G>A	p.Gly266Arg	missense_variant	Exon 6 of 7	1		ENSP00000388415.1
LIPA	ENST00000371837.5	c.628G>A	p.Gly210Arg	missense_variant	Exon 6 of 9	2		ENSP00000360903.1
LIPA	ENST00000456827.5	c.448G>A	p.Gly150Arg	missense_variant	Exon 5 of 8	3		ENSP00000413019.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G266R variant (also known as c.796G>A), located in coding exon 6 of the LIPA gene, results from a G to A substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	4.6	H;.;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.4	D;D;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.95
MutPred		0.86		Gain of helix (P = 0.0349);.;.;Gain of helix (P = 0.0349);
MVP		0.95
MPC		0.68
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.92
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: -26

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

Other links and lift over

dbSNP: rs267607218; hg19: chr10-90983467;