chr10-89223710-C-A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000235.4(LIPA):c.796G>T(p.Gly266*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000806 in 1,612,760 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. G266G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000235.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- lysosomal acid lipase deficiencyInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
- cholesteryl ester storage diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Wolman diseaseInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LIPA | ENST00000336233.10 | c.796G>T | p.Gly266* | stop_gained | Exon 7 of 10 | 1 | NM_000235.4 | ENSP00000337354.5 | ||
LIPA | ENST00000428800.5 | c.796G>T | p.Gly266* | stop_gained | Exon 6 of 7 | 1 | ENSP00000388415.1 | |||
LIPA | ENST00000371837.5 | c.628G>T | p.Gly210* | stop_gained | Exon 6 of 9 | 2 | ENSP00000360903.1 | |||
LIPA | ENST00000456827.5 | c.448G>T | p.Gly150* | stop_gained | Exon 5 of 8 | 3 | ENSP00000413019.2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152040Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250494 AF XY: 0.00000737 show subpopulations
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460720Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726720 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74248 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Published functional studies found this variant is associated with reduced lysosomal acid lipase activity (Vinje T et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 23928541, 28881270, 29196158, 26252914, 22227072, 30684275, 8617513, 33857477, 8254026) -
Cholesteryl ester storage disease Pathogenic:2
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. -
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Cholesteryl ester storage disease;C0043208:Wolman disease Pathogenic:1
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Wolman disease Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gly266*) in the LIPA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LIPA are known to be pathogenic (PMID: 23485521). This variant is present in population databases (rs267607218, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with lysosomal acid lipase (LAL) deficiency (PMID: 28881270, 30684275). ClinVar contains an entry for this variant (Variation ID: 78). 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. -
Lysosomal acid lipase deficiency Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at