ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr)

gnomAD frequency: 0.00001  dbSNP: rs193922566
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000030122 SCV001960921 likely pathogenic Hypercholesterolemia, familial, 1 2021-06-08 reviewed by expert panel curation NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, PP3, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM1 - Variant meets PM2 and alters Cys340, one of the cysteine residues listed. PM2 - PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL: 0,98. PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID: 30592178 who fulfills DLCN criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases with clinical FH criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000722113 SCV000052777 pathogenic Familial hypercholesterolemia 2020-11-16 criteria provided, single submitter clinical testing Variant summary: LDLR c.1055G>A (p.Cys352Tyr) results in a non-conservative amino acid change located in the EGF-like domain and EGF-like calcium-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several variants at the same codon have been associated with Familial Hypercholesterolemia (C352R, C352F, C352S, C352W), as well as the immediately adjacent codons, suggesting the locus is important for gene function.The variant allele was found at a frequency of 8e-06 in 250860 control chromosomes. c.1055G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (example, Hobbs_1992, Kolansky_2008, Ahmad_2012, Vaca_2011, Magana Torres_2014, Tichy_2012, Alonso_2009, Junyent_2010, Mabuchi_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal LDL receptor activity (Kolansky_2008). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
LDLR-LOVD, British Heart Foundation RCV000030122 SCV000295167 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000413322 SCV000491200 likely pathogenic not provided 2023-03-01 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 FH Mexico-2 and C331Y due to alternate nomenclature; This variant is associated with the following publications: (PMID: 1301956, 19026292, 19318025, 22698793, 32331935, 30592178, 32719484, 31491741, 34037665, 25234566, 2988123, 12459547, 25014035, 28391882, 19717150, 29576406, 23064986, 21722902)
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation RCV000030122 SCV000540786 likely pathogenic Hypercholesterolemia, familial, 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys340 and Cys352.
Invitae RCV000722113 SCV000544690 pathogenic Familial hypercholesterolemia 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 352 of the LDLR protein (p.Cys352Tyr). This variant is present in population databases (rs193922566, gnomAD 0.006%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 1301956, 19717150, 21722902, 22698793, 23064986, 25234566). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys331Tyr. ClinVar contains an entry for this variant (Variation ID: 36450). 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%. For these reasons, this variant has been classified as Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000030122 SCV000607552 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000030122 SCV000748047 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Fulgent Genetics, Fulgent Genetics RCV000030122 SCV000894172 pathogenic Hypercholesterolemia, familial, 1 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000722113 SCV000909469 pathogenic Familial hypercholesterolemia 2023-04-11 criteria provided, single submitter clinical testing This missense variant (also known as p.Cys331Tyr in the mature protein and as FH Mexico-2) replaces cysteine with tyrosine at codon 352 in the EGF-like repeat A 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). An experimental study has shown that this variant results in a significantly reduced LDLR activity in cells from a patient compound heterozygous for this variant and p.Cys364Arg (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 21722902, 22698793, 23064986, 32331935, 33533259, 34037665, 35929461; Color internal data). This variant has also been observed in both the compound heterozygous and homozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 1301956, 25234566). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 25234566). This variant has been identified in 2/250660 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon: p.Cys352Phe, p.Cys352Trp, and p.Cys352Ser, are considered to be disease-causing (ClinVar variation ID: 251619, 251622, 251617), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.
3billion RCV000030122 SCV002318891 pathogenic Hypercholesterolemia, familial, 1 2022-03-22 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000036450, PMID:1301956). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000251617,VCV000251618,VCV000251619,VCV000251622, PMID:21376320,17347910, 20809525, 9974426). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98>=0.6, 3CNET: 0.99>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics RCV002408481 SCV002715534 pathogenic Cardiovascular phenotype 2022-06-10 criteria provided, single submitter clinical testing The p.C352Y pathogenic mutation (also known as c.1055G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1055. The cysteine at codon 352 is replaced by tyrosine, 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) (Vill&eacute;ger L. Hum Mutat. 2002;20(2):81-7). This particular mutation (also reported as p.C331Y and Mexico-2) has been observed in multiple FH cohorts (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Alonso R et al. em>Clin. Biochem. 009;42:899-903; Vaca G et al. Atherosclerosis. 2011;218:391-6; Ahmad Z et al. Circ Cardiovasc Genet. 2012;5:666-75; Tich&yacute; L et al. Atherosclerosis. 2012;223:401-8). This alteration has also been detected in the homozygous state in a proband with homozygous FH, and segregated with disease on both sides of the family, although with incomplete penetrance (Maga&ntilde;a Torres MT et al. J Clin Lipidol. 2014;8:525-7). In addition, this mutation segregated with disease in one small family tested by our laboratory. Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like domain (Ambry internal data). Furthermore, several alterations in the same codon (p.C352S, p.C352W, p.C352R, and p.C352F) have also been associated with FH (Bertolini S et al. Arterioscler Thromb Vasc Biol. 1999;19(2)408-18; Widhalm K et al. J Inherit Metab Dis. 2007;30(2):239-47; Marduel M et al. Hum. Mutat. 2010;31(11):E1811-24; Chiou KR et al. Atherosclerosis. 2011;216:383-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
New York Genome Center RCV000030122 SCV002764476 likely pathogenic Hypercholesterolemia, familial, 1 2020-11-27 criteria provided, single submitter clinical testing The c.1055G>A(p.Cys352Tyr) missense variant (also previously known asp.Cys331Tyr and FH-Mexico-2 allele) is localized in exon 7 of 18 of LDLR in the EGF-like domain. This variant has been identified in multiple individuals diagnosed with hypercholesterolemia in heterozygous, homozygous and compound heterozygous states [PMIDs:1301956, 19717150, 21722902, 22698793, 23064986, 25234566]. Experimental studies have shown that this variant results in a significantly reduced LDLR activity in cells from patients [PMIDs: 1301956, 19026292]. This variant is absent in gnomADv3 and present in gnomADv2 at a very low frequency (2/250660alleles, allele frequency = 0.000007979; no homozygoytes) indicating it is not a common benign variant in the populations represented in this database. In silico predictors suggest this variant is Damaging (Provean; score: -10.55;SIFT; score:0). This variant has been reported in Clinvar as a Pathogenic /Likely Pathogenic variant [Variation ID:36450]. Missense variants at the same residue (Cys352Ser, Cys352Arg, Cys352Phe, Cys352Trp) have also been reported in affected individuals with familial hypercholesterolemia. Given the current evidence regarding its pathogenicity, the c.1055G>A(p.Cys352Tyr) variant identified in the LDLR gene is reported as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003952374 SCV004767085 likely pathogenic LDLR-related disorder 2023-11-05 criteria provided, single submitter clinical testing The LDLR c.1055G>A variant is predicted to result in the amino acid substitution p.Cys352Tyr. This variant was reported in patients with hypercholesterolemia (For example, reported as FH Mexico-2 or C331Y in Hobbs et al. 1992. PubMed ID: 1301956; Sturm. 2021. PubMed ID: 34037665). Incomplete penetrance was noted in a family (Magaña Torres et al. 2014. PubMed ID: 25234566). Of note, other missense variants affecting the same amino acid (p.Cys352Ser, p.Cys352Arg, p.Cys352Phe) have also been reported as causative for hypercholesterolemia (HGMD database; Hobbs et al. 1992. PubMed ID: 1301956). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11221442-G-A). This variant is interpreted as likely pathogenic or pathogenic in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/RCV000030122.12/). This variant is interpreted as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000030122 SCV000606301 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000413322 SCV000925131 pathogenic not provided 2017-11-06 no assertion criteria provided provider interpretation

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