Submissions for variant NM_000527.5(LDLR):c.1468T>C (p.Trp490Arg)

dbSNP: rs730880130

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000157290	SCV000295452	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000157290	SCV000322956	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000157290	SCV000503352	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH/Software predictions: Conflicting
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034638	SCV000752409	pathogenic	Familial hypercholesterolemia	2022-02-09	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LDLR function (PMID: 23021490, 25386756). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 180402). This variant is also known as W469R. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17765246, 23021490, 23375686, 31345425; Invitae). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 490 of the LDLR protein (p.Trp490Arg).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000157290	SCV001432634	likely pathogenic	Hypercholesterolemia, familial, 1	2019-03-13	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001034638	SCV001821352	pathogenic	Familial hypercholesterolemia	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1468T>C (p.Trp490Arg) results in a non-conservative amino acid change located in the LDL-receptor class B3 domain (LOVD database) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. c.1468T>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Bourbon_2008, Silva_2012, Bertolini_2013, Futema_2021). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in only 5% of normal LDLR activity and that this mutant protein is mainly retained in the ER (example, Silva_2012, Etxebarria_2014). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002390373	SCV002701263	pathogenic	Cardiovascular phenotype	2021-11-19	criteria provided, single submitter	clinical testing	The p.W490R pathogenic mutation (also known as c.1468T>C), located in coding exon 10 of the LDLR gene, results from a T to C substitution at nucleotide position 1468. The tryptophan at codon 490 is replaced by arginine, an amino acid with dissimilar properties. This variant (also referred to as p.W469R) has been detected in unrelated individuals reported to have familial hypercholesterolemia (FH), and was reported to segregate with disease in families (Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Silva S et al. Atherosclerosis, 2012 Nov;225:128-34; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Trinder M et al. J Am Coll Cardiol, 2019 07;74:512-522; Futema M et al. Atherosclerosis, 2021 02;319:108-117). This variant has also been detected in trans with a second mutation in the LDLR gene in an individual reported to have homozygous FH (Gao M et al. Front Pediatr, 2020 Oct;8:535949). In in vitro functional studies, this variant resulted in impaired protein expression and activity (Silva S et al. Atherosclerosis, 2012 Nov;225:128-34; Etxebarria A et al. PLoS One, 2014 Nov;9:e112677). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Blueprint Genetics	RCV000157290	SCV000207021	pathogenic	Hypercholesterolemia, familial, 1	2014-11-27	no assertion criteria provided	clinical testing