Submissions for variant NM_000527.5(LDLR):c.1588T>G (p.Phe530Val)

gnomAD frequency: 0.00002  dbSNP: rs875989924

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034676	SCV000834964	likely pathogenic	Familial hypercholesterolemia	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 530 of the LDLR protein (p.Phe530Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. 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: 226361). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV002399778	SCV002706006	uncertain significance	Cardiovascular phenotype	2021-03-11	criteria provided, single submitter	clinical testing	The p.F530V variant (also known as c.1588T>G), located in coding exon 11 of the LDLR gene, results from a T to G substitution at nucleotide position 1588. The phenylalanine at codon 530 is replaced by valine, an amino acid with highly similar properties. This variant was reported in two cases from a New Zealand familial hypercholesterolemia cohort; however, no clinical details were provided (Laurie et al., J Genet Disor Genet Rep. 2018; 7:1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000211668	SCV002788464	uncertain significance	Hypercholesterolemia, familial, 1	2021-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV004589907	SCV005079100	uncertain significance	not provided	2024-07-05	criteria provided, single submitter	clinical testing	Identified in patients with familial hypercholesterolemia in published literature (Laurie et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(F509V); This variant is associated with the following publications: (PMID: 37409534, LaurieAD2018]Article])
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211668	SCV000268623	pathogenic	Hypercholesterolemia, familial, 1	2016-01-14	no assertion criteria provided	clinical testing