10-89225168-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000235.4(LIPA):āc.599T>Cā(p.Leu200Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,102 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L200L) has been classified as Likely benign.
Frequency
Consequence
NM_000235.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LIPA | NM_000235.4 | c.599T>C | p.Leu200Pro | missense_variant | 6/10 | ENST00000336233.10 | |
LIPA | NM_001127605.3 | c.599T>C | p.Leu200Pro | missense_variant | 6/10 | ||
LIPA | NM_001288979.2 | c.251T>C | p.Leu84Pro | missense_variant | 4/8 | ||
LIPA | XM_024448023.2 | c.599T>C | p.Leu200Pro | missense_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LIPA | ENST00000336233.10 | c.599T>C | p.Leu200Pro | missense_variant | 6/10 | 1 | NM_000235.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251462Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11AN XY: 727234
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74390
ClinVar
Submissions by phenotype
Wolman disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2023 | Variant summary: LIPA c.599T>C (p.Leu200Pro) results in a non-conservative amino acid change located in the Alpha/beta hydrolase fold-1 domain (IPR000073) of the encoded protein sequence. This variant is also known as L179P. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251462 control chromosomes (gnomAD). c.599T>C has been reported in the literature in individuals affected with Lysosomal Acid Lipase Deficiency (examples: Pullinger_2015, Ambler_2012, Anderson_1994, Maslen_1995). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Vinje_2019) . Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2023 | 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. This missense change has been observed in individual(s) with cholesterol ester storage disease (CESD) or Wolman disease (PMID: 8146180, 8598644, 8617513, 23430518). It has also been observed to segregate with disease in related individuals. This variant is also known as L179P. ClinVar contains an entry for this variant (Variation ID: 77). Experimental studies have shown that this missense change affects LIPA function (PMID: 7499245, 10562460). For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs121965086, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 200 of the LIPA protein (p.Leu200Pro). - |
Lysosomal acid lipase deficiency Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 07, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at