Submissions for variant NM_000527.5(LDLR):c.1730G>C (p.Trp577Ser)

gnomAD frequency: 0.00001  dbSNP: rs138947766

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238353	SCV000295620	likely pathogenic	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	RCV000238353	SCV000503400	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 and functional study "GFP fused protein not transported to cell surface"/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000238353	SCV000583872	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Invitae	RCV001377886	SCV001575334	likely pathogenic	Familial hypercholesterolemia	2020-09-20	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs138947766, ExAC 0.001%). This variant has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 8697568, 11810272, Invitae). This variant is also known as W556S. ClinVar contains an entry for this variant (Variation ID: 252003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 28126585, 27919346, 11916007, 27294413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This sequence change replaces tryptophan with serine at codon 577 of the LDLR protein (p.Trp577Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine.
MGZ Medical Genetics Center	RCV000238353	SCV002579828	likely pathogenic	Hypercholesterolemia, familial, 1	2021-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401945	SCV002713860	pathogenic	Cardiovascular phenotype	2022-10-05	criteria provided, single submitter	clinical testing	The p.W577S pathogenic mutation (also known as c.1730G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1730. The tryptophan at codon 577 is replaced by serine, an amino acid with highly dissimilar properties. This alteration impacts the YWTD motif in LDLR class B repeat five. This variant has been detected in multiple individuals with familial hypercholesterolemia (FH) and has been shown to be a founder mutation responsible for ~12% of Danish FH cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Jensen HK et al. Atherosclerosis, 1997 May;131:67-72). Functional studies indicate that this alteration causes a trafficking defect (Jensen HK et al. Atherosclerosis, 1997 May;131:67-72), Another pathogenic mutation, p.W577R, has been described in the same codon (Gutierrez G et al. Hum. Mutat., 2000 Oct;16:374). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003897581	SCV004711912	pathogenic	LDLR-related condition	2023-11-22	criteria provided, single submitter	clinical testing	The LDLR c.1730G>C variant is predicted to result in the amino acid substitution p.Trp577Ser. This variant (also known as W556S) was reported in individuals with autosomal dominant familial hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Table S1, Benedek et al. 2021. PubMed ID: 33955087; Table S1, Leren et al. 2021. PubMed ID: 33740630; Table 2, Miroshnikova et al. 2021. PubMed ID: 33269076). Other missense variants impacting this residue (p.Trp577Gly, p.Trp577Cys, p.Trp577Arg) have also been reported as pathogenic in individuals with hypercholesterolemia phenotypes (Table S1, Leren et al. 2021. PubMed ID: 33740630; eTable 1, Sturm. 2021. PubMed ID: 34037665). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238353	SCV000606501	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research