ClinVar Miner

Submissions for variant NM_000235.4(LIPA):c.599T>C (p.Leu200Pro)

gnomAD frequency: 0.00001  dbSNP: rs121965086
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000000096 SCV000793037 likely pathogenic Lysosomal acid lipase deficiency 2017-08-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000000095 SCV000931711 pathogenic Wolman disease 2023-07-03 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects LIPA function (PMID: 7499245, 10562460). ClinVar contains an entry for this variant (Variation ID: 77). This variant is also known as L179P. 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 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000000095 SCV003844837 pathogenic Wolman disease 2023-02-16 criteria provided, single submitter clinical testing 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.
GENinCode PLC RCV000000096 SCV005622670 pathogenic Lysosomal acid lipase deficiency 2023-11-16 criteria provided, single submitter clinical testing The c.599T>C p.(Leu200Pro) variant in LIPA is a missense variant that has been seen in several patients with a clinical diagnosis of Lysosomal Acid Lipase Deficiency who also carry a second pathogenic LIPA variant (PM3_STRONG, PP4_SUPPORTING; PMIDs 8146180, 8598644, 23430518, 26350820). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002458 in European (non-Finnish) population (PM2_MODERATE). Functional studies demonstrated loss of enzyme activity in vitro (PS3_STRONG; PMIDs 7499245, 8146180, 31131398, 31180157) and the REVEL score is 0.896 (PP3_SUPPORTING). Based on the evidence listed above, this variant has been classified as pathogenic.
OMIM RCV000000095 SCV000020238 pathogenic Wolman disease 1995-01-01 no assertion criteria provided literature only
OMIM RCV000000096 SCV000020239 pathogenic Lysosomal acid lipase deficiency 1995-01-01 no assertion criteria provided literature only
Natera, Inc. RCV000000096 SCV002091377 pathogenic Lysosomal acid lipase deficiency 2020-07-07 no assertion criteria provided clinical testing

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