Submissions for variant NM_000527.5(LDLR):c.2547+5G>A

dbSNP: rs879255226

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321571	SCV001512407	pathogenic	Familial hypercholesterolemia	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 27816806; internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 440702). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002264950	SCV002546741	likely pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27816806)
Ambry Genetics	RCV002431470	SCV002740622	uncertain significance	Cardiovascular phenotype	2021-02-02	criteria provided, single submitter	clinical testing	The c.2547+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 17 in the LDLR gene. This variant was detected in a child with homozygous familial hypercholesterolemia, including significantly elevated cholesterol levels, xanthomas, and corneal arcus; her parents were reportedly consanguineous with elevated LDL cholesterol levels (Setia N et al. Atherosclerosis, 2016 12;255:31-36). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323578	SCV004028786	uncertain significance	not specified	2023-07-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.2547+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2547+5G>A has been reported in the literature in a three year old individual affected with familial hypercholesterolemia and her parents were reportedly consanguineous with elevated LDL cholesterol levels (example: Setia_2016). This report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27816806). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508841	SCV000606668	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research