Submissions for variant NM_000527.5(LDLR):c.400T>C (p.Cys134Arg)

dbSNP: rs875989900

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211566	SCV000294685	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000494460	SCV000582589	likely pathogenic	not provided	2023-06-12	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; Also known as p.(C113R); This variant is associated with the following publications: (PMID: 26582918, 25921077, 7548065, 18325082, 23375686, 12459547, 2988123, 7603991, 29233637, 15256764, 12417285, 31447099, 10735632, 32759540, 32770674, 12730724, 30415195, 11462246, 34037665, 28179607, 7979249, 28349240)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844756	SCV000711781	likely pathogenic	Homozygous familial hypercholesterolemia	2017-08-15	criteria provided, single submitter	clinical testing	The p.Cys134Arg (previously p.Cys113Arg) variant in LDLR has been reported in >4 individuals with familial hypercholesterolemia (FH) and segregated with disease with 2 affected relatives from 1 family (Lombardi 2000, Nauck 2001, El Messal 2 003, Han 2015, ClinVar: Variation ID 226322). It has also been identified in 1/1 11580 European chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org/; dbSNP rs875989900). Computational prediction tools and conservation analysis suggest that the p.Cys134Arg variant may impact the prote in. Additionally, other missense variants at this position (p.Cys134Tyr, p.Cys13 4Phe, p.Cys134Gly and p.Cys134Trp) have been reported in individuals with famili al hypercholesterolemia (Human Gene Mutation Database: Stenson et al., 2017), In summary, although additional studies are required to fully establish its clinic al significance, the p.Cys134Arg variant is likely pathogenic for autosomal domi nant FH. ACMG/AMP criteria applied: PS4_Moderate, PM2, PM5_Supporting, PP3.
Invitae	RCV000775036	SCV000752410	pathogenic	Familial hypercholesterolemia	2023-10-10	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 134 of the LDLR protein (p.Cys134Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 10735632, 11462246, 12730724, 25921077). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys113Arg. ClinVar contains an entry for this variant (Variation ID: 226322). 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. 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.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11462246, 23375686), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000775036	SCV000909133	pathogenic	Familial hypercholesterolemia	2022-10-24	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 134 in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. This variant is also known as p.Cys113Arg in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Different missense variants occurring at the same codon (p.Cys134Tyr, p.Cys134Phe, p.Cys134Trp) are known to be disease-causing (ClinVar variation ID: 251203, 251204, 251205). This p.Cys134Arg variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 10735632, 11462246, 12417285, 12730724, 15256764, 25921077, 29233637, 32143996, 32759540). It has also been observed to segregate with high LDL-C levels and xanthomas in three related individuals (PMID: 25921077). This variant has been identified in 1/251176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic.
Ambry Genetics	RCV002372212	SCV002624552	pathogenic	Cardiovascular phenotype	2023-03-09	criteria provided, single submitter	clinical testing	The p.C134R pathogenic mutation (also known as c.400T>C), located in coding exon 4 of the LDLR gene, results from a T to C substitution at nucleotide position 400. The cysteine at codon 134 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been described in patients with familial hypercholesterolemia (FH) from various ethnic groups (Lombardi MP et al. Clin Genet. 2000;57:116-24; Nauck MS et al. Hum Mutat. 2001;18:165-6; El Messal M et al. J Hum Genet. 2003;48:199-203; Han Y et al. Int J Pediatr Otorhinolaryngol. 2015;79:1148-51). Other alterations involving the same amino acid, p.C134F (c.401G>T), p.C134W (c.402C>G), and p.C134Y (c.401G>A), have also been reported in FH cohorts (Bertolini S et al. Atherosclerosis. 2013;227(2):342-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the LDLR class A repeat 3 (Ambry internal data). 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211566	SCV000268561	pathogenic	Hypercholesterolemia, familial, 1	2016-03-24	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211566	SCV000606104	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research