Submissions for variant NM_000527.5(LDLR):c.828C>G (p.Cys276Trp)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237617	SCV000295005	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	RCV000237617	SCV000503242	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1 , family members = 5 with co-segregation / previously described in association with FH / Software predictions: Conflicting
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237617	SCV000588521	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
All of Us Research Program, National Institutes of Health	RCV000237617	SCV004836951	likely pathogenic	Hypercholesterolemia, familial, 1	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 276 in the LDLR type A repeat 7 of the LDLR protein. This variant is also known as p.Cys255Trp in the mature protein and as FH Sassari-3 in the literature. 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 variant has been reported in at least 10 individuals affected with familial hypercholesterolemia (PMID: 10634824, 10978268, 19026292, 23375686, 24529145, 25461735, 28161202, 30293936) and was shown to segregate with disease in one family (PMID: 28161202). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Multiple different variants affecting the same codon, p.Cys276Gly, p.Cys276Arg, p.Cys276Tyr, and p.Cys276Ser, are considered to be disease-causing (ClinVar variation ID: 251480, 251479, 251481, 183096), indicating that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090223	SCV005837086	pathogenic	Familial hypercholesterolemia	2024-07-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 276 of the LDLR protein (p.Cys276Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10634824, 25461735, 32977124, 35913489). ClinVar contains an entry for this variant (Variation ID: 251482). 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.Cys276 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10978268). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237617	SCV000606241	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research