Submissions for variant NM_000527.5(LDLR):c.1999T>C (p.Cys667Arg)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238269	SCV000295809	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238269	SCV000322995	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 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	RCV000238269	SCV000503449	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000238269	SCV000540851	likely pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing	Disrupt disulfide bridge between Cys667 and Cys681.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000238269	SCV000588626	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000238269	SCV000748170	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821494	SCV000962252	pathogenic	Familial hypercholesterolemia	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 667 of the LDLR protein (p.Cys667Arg). This variant is present in population databases (rs150021927, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9412789, 17765246, 21310417, 23064986, 27824480). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys646Arg. ClinVar contains an entry for this variant (Variation ID: 252163). 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 affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys667 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9727746, 11313767, 15701167, 18263977, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001812663	SCV002049245	likely pathogenic	not provided	2021-11-11	criteria provided, single submitter	clinical testing	The LDLR c.1999T>C; p.Cys667Arg variant (rs150021927) is reported in the literature in more than ten individuals affected with high LDL-C (Lange, 2014, Sturm 2021). Moreover, this variant has been identified as the only co-segregating allele within a large familial hypercholesterolemia family based on homozygosity (Vergopoulos,1997). This variant is also reported in ClinVar (Variation ID: 334184). This variant is only observed on one allele (1/251398 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The cysteine at codon 667 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.987). Based on available information, this variant is considered to be likely pathogenic.
3billion	RCV000238269	SCV002573022	pathogenic	Hypercholesterolemia, familial, 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (3billion dataset). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252163). Different missense changes at the same codon (p.Cys667Phe, p.Cys667Ser, p.Cys667Trp, p.Cys667Tyr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003689 , VCV000252162 , VCV000252165 , VCV000252168). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000238269	SCV002811051	pathogenic	Hypercholesterolemia, familial, 1	2021-08-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001812663	SCV003761994	pathogenic	not provided	2023-01-26	criteria provided, single submitter	clinical testing	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; This variant is associated with the following publications: (PMID: 28895539, 25487149, 21310417, 22698793, 27824480, 30415195, 24507775, 17765246, 23064986, 9412789, 33740630, 34037665)
All of Us Research Program, National Institutes of Health	RCV000238269	SCV004825209	pathogenic	Hypercholesterolemia, familial, 1	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Cys646Arg in the mature protein) replaces cysteine with arginine at codon 667 in the EGF-like repeat C of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). 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). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 17765246, 21310417, 22698793, 23064986, 28895539, 34037665). This variant has also been observed in homozygous state in six individuals affected with severe homozygous familial hypercholesterolemia in one large family, a phenotype expected of having two deleterious LDLR variants (PMID: 9412789). It has been shown that this variant segregates with disease in multiple affected individuals in one large family (PMID: 9412789). This variant has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149, 27050191). This variant has been identified in 1/251398 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Cys667Tyr, is considered to be disease-causing (ClinVar variation ID: 3689), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001812663	SCV005198661	likely pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238269	SCV000606573	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research