Submissions for variant NM_000235.4(LIPA):c.966+3A>T

gnomAD frequency: 0.00015  dbSNP: rs201242614

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592075	SCV000704384	uncertain significance	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000666174	SCV000790421	uncertain significance	Lysosomal acid lipase deficiency	2017-03-20	criteria provided, single submitter	clinical testing
Invitae	RCV002532444	SCV001415552	uncertain significance	Wolman disease	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 9 of the LIPA gene. It does not directly change the encoded amino acid sequence of the LIPA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201242614, gnomAD 0.03%). This variant has been observed in individual(s) with hypercholesterolemia (PMID: 27423329). ClinVar contains an entry for this variant (Variation ID: 499076). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV000666174	SCV002792187	uncertain significance	Lysosomal acid lipase deficiency	2021-07-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230551	SCV003928865	uncertain significance	not specified	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: LIPA c.966+3A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 251392 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LIPA causing Lysosomal Acid Lipase Deficiency (0.00015 vs 0.0027), allowing no conclusion about variant significance. c.966+3A>T has been reported in the literature in an individual affected with familial hypercholesterolemia (example:Sjouke_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Lysosomal Acid Lipase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000666174	SCV002091321	uncertain significance	Lysosomal acid lipase deficiency	2020-01-31	no assertion criteria provided	clinical testing