Submissions for variant NM_015627.3(LDLRAP1):c.533-1G>A

dbSNP: rs762148512

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050968	SCV001215101	likely pathogenic	Hypercholesterolemia, familial, 4	2023-02-09	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 5 of the LDLRAP1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLRAP1 are known to be pathogenic (PMID: 11326085, 12464675). This variant is present in population databases (rs762148512, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of dyslipidemia (PMID: 32041611). ClinVar contains an entry for this variant (Variation ID: 847427). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001832468	SCV002600758	likely pathogenic	Familial hypercholesterolemia	2022-10-03	criteria provided, single submitter	clinical testing	Variant summary: LDLRAP1 c.533-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site and two predict the variant creates a new exonic 3' acceptor site 2 nucleotides downstream. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes (gnomAD). c.533-1G>A has been reported in the literature in at least one individual undergoing multigene panel testing for dyslipidemias and metabolic disorders, however the clinical phenotype of the individual(s) was not specified (e.g. Dron_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV001050968	SCV004172335	likely pathogenic	Hypercholesterolemia, familial, 4	2023-04-11	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001832468	SCV002085936	likely pathogenic	Familial hypercholesterolemia	2020-10-28	no assertion criteria provided	clinical testing