Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002425596 | SCV002730681 | uncertain significance | Cardiovascular phenotype | 2022-01-03 | criteria provided, single submitter | clinical testing | The p.P336L variant (also known as c.1007C>T), located in coding exon 9 of the LIPA gene, results from a C to T substitution at nucleotide position 1007. The proline at codon 336 is replaced by leucine, an amino acid with similar properties. This variant was reported in a heterozygous individual with hypercholesterolemia with no additional variants reported, and functional studies showed approximately 40% of wild-type enzyme activity (Vinje T et al. Mol Genet Metab, 2018 02;123:169-176). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV003101119 | SCV003451248 | uncertain significance | Wolman disease | 2024-12-02 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 336 of the LIPA protein (p.Pro336Leu). This variant is present in population databases (rs770407719, gnomAD 0.008%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 29196158). ClinVar contains an entry for this variant (Variation ID: 1787481). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LIPA protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LIPA function (PMID: 29196158). 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. |