Submissions for variant NM_000527.5(LDLR):c.1796T>C (p.Leu599Ser)

dbSNP: rs879255025

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237846	SCV000295662	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237846	SCV000503415	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 5 , family member = 1 with co-segregation / FH-London-5, 5 to 15% LDLR Activity/Software predictions: Conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237846	SCV000583884	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237846	SCV000607641	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237846	SCV001432596	pathogenic	Hypercholesterolemia, familial, 1	2019-01-22	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518488	SCV003443165	uncertain significance	Familial hypercholesterolemia	2024-10-02	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 599 of the LDLR protein (p.Leu599Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 12436241, 19318025, 27680772, 31345425). This variant is also known as L578S. ClinVar contains an entry for this variant (Variation ID: 252035). 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 LDLR protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV003165670	SCV003912555	likely pathogenic	Cardiovascular phenotype	2022-12-15	criteria provided, single submitter	clinical testing	The p.L599S variant (also known as c.1796T>C), located in coding exon 12 of the LDLR gene, results from a T to C substitution at nucleotide position 1796. The leucine at codon 599 is replaced by serine, an amino acid with dissimilar properties. This variant (also referred to as L578S and FH London-5) co-occurred with an LDLR gross deletion in an individual with total cholesterol of 27mmol/L and reported LDL-R activity 5-15% of normal (Hobbs HH et al. Hum Mutat, 1992;1:445-66, Webb JC et al. J Lipid Res, 1996 Feb;37:368-81). This variant has also been detected in additional individuals from familial hypercholesterolemia (FH) cohorts with suspected heterozygous FH (Webb JC et al. J Lipid Res, 1996 Feb;37:368-81; Amsellem S et al. Hum Genet, 2002 Dec;111:501-10; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Laurie AD et al. Clin Biochem, 2009 Apr;42:528-35; Trinder M et al. J Am Coll Cardiol. 2019 Jul;74(4):512-522). Based on internal structural analysis, this variant is predicted to be destabilizing (Jeon H et al. Nat Struct Biol. 2001 Jun;8(6):499-504; Rudenko G et al. Science. 2002 Dec;298(5602):2353-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.