Submissions for variant NM_000235.4(LIPA):c.379C>T (p.Arg127Trp)

gnomAD frequency: 0.00005  dbSNP: rs140686447

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002509479	SCV000754531	uncertain significance	Wolman disease	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 127 of the LIPA protein (p.Arg127Trp). This variant is present in population databases (rs140686447, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with LIPA-related conditions. ClinVar contains an entry for this variant (Variation ID: 528226). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects LIPA function (PMID: 29196158, 31180157). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000633314	SCV002790886	uncertain significance	Lysosomal acid lipase deficiency	2022-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509479	SCV002819760	likely pathogenic	Wolman disease	2022-12-23	criteria provided, single submitter	clinical testing	Variant summary: LIPA c.379C>T (p.Arg127Trp) results in a non-conservative amino acid change located in the Alpha/beta hydrolase fold-1(IPR000073) of the encoded protein sequence. 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 4.8e-05 in 251444 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (4.8e-05 vs 0.0027), allowing no conclusion about variant significance. c.379C>T has been reported in the literature as a heterozygous genotype in at least one individual affected with Hypercholesterolemia (Vinje_2018). This report does not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. Two publications reports experimental evidence evaluating an impact on enzymatic activity (Vinje_2018 and DelAngel_2019). The most pronounced variant effect results in <10% of normal Lysosomal acidic lipase activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
New York Genome Center	RCV000633314	SCV003925409	uncertain significance	Lysosomal acid lipase deficiency	2022-02-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000633314	SCV001453549	uncertain significance	Lysosomal acid lipase deficiency	2020-09-16	no assertion criteria provided	clinical testing