Submissions for variant NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys)

gnomAD frequency: 0.00001  dbSNP: rs879254867

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237729	SCV000295371	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	RCV000237729	SCV000503334	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 10 , family members = 5 with co-segregation / previously described in association with FH / Software predictions: Damaging
Invitae	RCV000791422	SCV000544664	pathogenic	Familial hypercholesterolemia	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 443 of the LDLR protein (p.Trp443Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 9664576, 9727746, 11196104, 22390909). This variant is also known as p.Trp422Cys. ClinVar contains an entry for this variant (Variation ID: 251792). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Trp443 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28458923), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000494596	SCV000583130	likely pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vivo analysis suggest a statistically significant elevation of LDL-C levels in patients with W443C compared to wild type patients (Huijgen et al., 2021); Also known as W422C and FH North Platt; This variant is associated with the following publications: (PMID: 31447099, 32220565, 9664576, 1301956, 9727746, 11810272, 21382890, 11845603, 11196104, 12436241, 33111339, 34037665, 34363016, 32770674, 33740630, 22390909)
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237729	SCV000583822	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844741	SCV000731444	pathogenic	Homozygous familial hypercholesterolemia	2017-01-31	criteria provided, single submitter	clinical testing	The p.Trp443Cys variant in LDLR has been reported in >90 individuals with famili al hypercholesterolemia (FH) and was absent from large population studies. In vi tro functional studies demonstrate that this variant results in reduced protein activity (Hobbs 1992). Computational prediction tools and conservation analysis suggest that the p.Trp443Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for FH in an autosomal dom inant manner based upon prevalence among probands, absence from controls, and fu nctional evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000494596	SCV001134249	pathogenic	not provided	2019-06-05	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/282626 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Multiple pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
CeGaT Center for Human Genetics Tuebingen	RCV000494596	SCV001246007	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	LDLR: PM1:Strong, PS1, PM2, PS4:Supporting
Color Diagnostics, LLC DBA Color Health	RCV000791422	SCV001346787	pathogenic	Familial hypercholesterolemia	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Trp422Cys in the mature protein) replaces tryptophan with cysteine at codon 443 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that human cells compound heterozygous for this variant and p.Pro685Leu show 5-15% LDLR activity (PMID: 1301956). This variant has been reported in over 90 individuals affected with familial hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909, 33740630). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237729	SCV001440625	pathogenic	Hypercholesterolemia, familial, 1	2019-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000494596	SCV001715488	likely pathogenic	not provided	2020-12-30	criteria provided, single submitter	clinical testing	PS3_moderate, PS4_moderate, PM2_supporting, PP3
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000237729	SCV001754788	pathogenic	Hypercholesterolemia, familial, 1	2020-03-19	criteria provided, single submitter	clinical testing	The c.1329G>C (p.Trp443Cys) variant in the LDLR gene results in an amino acid change at residue 443 from a tryptophan to a cysteine. This variant has been reported in multiple unrelated individuals and families with familial hypercholesterolemia (PMID: 1301956, 11196104, 9664576, 9727746, 22390909). It has not been observed in the population database (gnomAD). It is located within the functionally important LDL-receptor class B repeat 2 region of the encoded protein. Multiple lines of in silico algorithms predicts this p.Trp443Cys change to be deleterious. A different nucleotide change at the same position (c.1329G>T) resulting in the same amino acid change (p.Trp443Cys) is considered pathogenic. Another variant that changes the residue 443 from tryptophan to arginine has been reported as pathogenic (PMID: 28290784 and 28458923). Therefore, this variant c.1329G>C (p.Trp443Cys) in LDLR is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000791422	SCV002511543	pathogenic	Familial hypercholesterolemia	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1329G>C (p.Trp443Cys) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) 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 251246 control chromosomes (gnomAD). c.1329G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (e.g. Weiss_2000, Kusters_2013, Leren_2021). These data indicate that the variant is very likely to be associated with disease. Twelve ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002379064	SCV002691627	pathogenic	Cardiovascular phenotype	2021-04-10	criteria provided, single submitter	clinical testing	The p.W443C pathogenic mutation (also known as c.1329G>C), located in coding exon 9 of the LDLR gene, results from a G to C substitution at nucleotide position 1329. The tryptophan at codon 443 is replaced by cysteine, an amino acid with highly dissimilar properties, and is located in the EGF-like precursor domain. This alteration has been reported (also described as p.W422C and North Platt) in numerous individuals with familial hypercholesterolemia (FH) from a variety of ethnic backgrounds (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Vergotine J et al. S. Afr. Med. J., 2001 Dec;91:1053-9; van der Graaf A et al. Circulation, 2011 Mar;123:1167-73). An alternate change at this nucleotide, c.1329G>T, with the same amino acid substitution has also been detected in individuals with FH (Huijgen R et al. Eur. Heart J., 2012 Sep;33:2325-30). Furthermore, additional amino acid substitutions at this position, p.W443S and p.W443R, have been reported in FH cohorts (Sozen M et al. Atheroscler Suppl, 2004 Dec;5:7-11; Korneva VA et al. Cholesterol, 2017 Mar;2017:9375818). Internal structural analysis has also determined that this alteration disrupts the structure in a structural hotspot cluster (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000237729	SCV002786656	likely pathogenic	Hypercholesterolemia, familial, 1	2022-01-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000237729	SCV003827828	pathogenic	Hypercholesterolemia, familial, 1	2022-11-08	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237729	SCV000606396	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research