Submissions for variant NM_000527.5(LDLR):c.1056C>G (p.Cys352Trp)

dbSNP: rs13306515

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237561	SCV000295171	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237561	SCV000599358	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586287	SCV000697183	pathogenic	Familial hypercholesterolemia	2017-07-26	criteria provided, single submitter	clinical testing	Variant summary: The LDLR c.1056C>G (p.Cys352Trp) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in a large, broad control population, ExAC in 120928 control chromosomes. This variant was reported in multiple patients with familial hypercholesterolemia (FH), including a homozygous patient whose phenotype was more severe than the heterozygous patients (Bertolini_Atherosclerosis_2013, Fouchier_HG_2001), including . A functional study suggested that the variant causes a defective LDL receptor, though the data was not provided for independent assessment (Bertolini_Atherosclerosis_2013). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000237561	SCV001432585	pathogenic	Hypercholesterolemia, familial, 1	2019-01-23	criteria provided, single submitter	research
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000237561	SCV001653617	likely pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002401933	SCV002712277	pathogenic	Cardiovascular phenotype	2019-09-23	criteria provided, single submitter	clinical testing	The p.C352W pathogenic mutation (also known as c.1056C>G), located in coding exon 7 of the LDLR gene, results from a C to G substitution at nucleotide position 1056. The cysteine at codon 352 is replaced by tryptophan, an amino acid with highly dissimilar properties, and is located in an EGF-like domain. 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). This particular cysteine alteration (also referred to as C331W and FH Avellino-1) has been reported in the homozygous state in a pediatric patient reported to have a clinical diagnosis of homozygous familial hypercholesterolemia (FH) and significantly reduced LDL-receptor activity; however, experimental data were not shown (Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999;19:408-18). This variant has been detected in additional individuals from FH cohorts (Lombardi MP et al. Clin. Genet., 2000;57:116-24; Van Gaal LF et al. Mol. Cell. Probes, 2001;15:329-36; Bertolini S et al. Atherosclerosis, 2013;227:342-8; Gabová D et al. Physiol Res, 2017;66:75-84). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). In addition, other variants affecting this codon (e.g., p.C352Y and p.C352S) have also been reported in association with FH (Magaña Torres MT et al. J Clin Lipidol. 2014;8:525-7; Medeiros AM et al. Genet. Med. 2016;18:316-24). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV000237561	SCV005427584	pathogenic	Hypercholesterolemia, familial, 1	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 352 in the EGF-like repeat A of the LDLR protein. This variant is also known as p.Cys331Trp in the mature protein, and as FH Avellino-1 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 tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies in cultured fibroblasts from both heterozygous and homozygous individuals have shown that this variant causes a significant reduction in LDLR activity as well as LDL binding and internalization (PMID: 9974426, 11585102). This variant has been reported in more than 10 individuals affected with familial hypercholesterolemia (PMID: 10735632, 10978268, 11585102, 11810272, 11851376, 23375686, 27824480, 30710474, 31345425, 32977124, 34456200). This variant has also been observed in homozygous state in one individual affected with severe homozygous familial hypercholesterolemia (PMID: 9974426, 26723464, 36422519). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Tyr, p.Cys352Phe, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 36450, 251619, 251617), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237561	SCV000606302	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research