ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) (rs193922566)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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 Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000413322 SCV000491200 likely pathogenic not provided 2016-12-12 criteria provided, single submitter clinical testing The C352Y likely pathogenic variant in the LDLR gene (also reported as C331Y due to alternate nomenclature) has been reported previously in association with FH (Hobbs et al., 1992; Kolansky et al., 2008; Alonso et al., 2009; Tichy et al., 2012; Magana Torres et al., 2014). Initially, the C352Y variant was reported in several Hispanic individuals with FH (Hobbs et al., 1992; Kolansky et al., 2008; Alonso et al., 2009) and was also subsequently reported in a Czech individual with FH (Tichy et al., 2012). Most recently, the C352Y variant was reported to be homozygous in one individual with severe homozygous FH (Magana Torres et al., 2014). This variant was reported to be heterozygous in both parents, siblings, and the paternal grandmother; however, reduced penetrance was noted as the father and paternal grandmother who were heterozygous for the variant were asymptomatic (Magana Torres et al., 2014). Additionally, the C352Y variant has been reported as a likely pathogenic variant associated with FH by one other clinical laboratory in ClinVar (ClinVar SCV000052777.1; Landrum et al., 2016). The C352Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and was not observed with any significant frequency in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The C352Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and is located in the EGF-like 1 domain. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C352S, C352R, C352F, C352W) have been reported in the Human Gene Mutation Database in association with FH (Stenson et al., 2014); however, the pathogenicity of these variants has not been definitively determined.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000030122 SCV000540786 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys340 and Cys352.
Invitae RCV000722113 SCV000544690 pathogenic Familial hypercholesterolemia 2020-08-21 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 352 of the LDLR protein (p.Cys352Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs193922566, ExAC 0.009%). This variant has been reported in the literature segregating with the disease in a family with hypercholesterolemia where the proband was homozygous for this variant (PMID: 25234566), as well as in multiple unrelated individuals affected with hypercholesterolemia (PMID: 1301956, 19717150, 23064986, 22698793, 21722902). This variant is also known as p.Cys331Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 36450). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant has been reported in the literature segregating with the disease in one family and in multiple unrelated affected individuals. For these reasons, this variant has been classified as Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000030122 SCV000607552 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000030122 SCV000748047 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000030122 SCV000894172 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000722113 SCV000909469 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030122 SCV000606301 pathogenic Familial hypercholesterolemia 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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