Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| LDLR- |
RCV000237709 | SCV000295143 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
| Molecular Genetics Laboratory, |
RCV000237709 | SCV000540782 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | Disrupt disulfide bridge between Cys340 and Cys352. |
| Color Diagnostics, |
RCV000775249 | SCV000909507 | likely pathogenic | Familial hypercholesterolemia | 2020-03-25 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Cys319Tyr in the mature protein) replaces cysteine with tyrosine at codon 340 of the LDLR 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 performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in multiple individuals diagnosed with familial hypercholesterolemia (PMID: 15241806, 27824480). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Labcorp Genetics |
RCV000775249 | SCV002211499 | pathogenic | Familial hypercholesterolemia | 2024-11-21 | 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 340 of the LDLR protein (p.Cys340Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 27824480, 30592178). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 251600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. |
| Ambry Genetics | RCV002365245 | SCV002659632 | pathogenic | Cardiovascular phenotype | 2023-04-17 | criteria provided, single submitter | clinical testing | The c.1019G>A (p.C340Y) alteration is located in exon 7 (coding exon 7) of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 1019, causing the cysteine (C) at amino acid position 340 to be replaced by a tyrosine (Y). This variant was not reported in population-based 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, 2002). This variant (also referred to as p.C319Y) has been detected in several individuals with FH or from FH cohorts (Mozas, 2004; Gabová, 2017; Chan, 2019). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of the EGF-like 1 domain (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
| All of Us Research Program, |
RCV000237709 | SCV004820252 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2023-11-14 | criteria provided, single submitter | clinical testing | The c.1019G>A (p.Cys340Tyr) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in in at least ten unrelated individuals with Familial Hypercholesterolemia (FH) (PMID:34834584, 30592178, 27824480, 15241806, 35560019, 33391333). Another study reports that this variant has been identified in three Slovak probands with FH and three relatives, however the phenotype of the relatives are not clear (PMID: 27824480). 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-silico computational prediction tools suggest that the p.Cys340Tyr variant may have deleterious effect on the protein function (REVEL score: 0.923). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 251600). Therefore, the c.1019G>A (p.Cys340Tyr) variant in the LDLR gene is classified as likely pathogenic. |
| Laboratory for Molecular Medicine, |
RCV004017548 | SCV004848201 | likely pathogenic | Homozygous familial hypercholesterolemia | 2021-02-22 | criteria provided, single submitter | clinical testing | The p.Cys340Tyr variant in LDLR has been reported in 5 individuals with hypercholesterolemia and segregated with disease in 3 affected relatives (Mozas 2014, Gabcova 2017, Chan 2019). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 251600). Three additional variants at this codon have been reported in individuals with hypercholesterolemia (p.Cys340Phe, p.Cys340Trp, and p.Cys340Leu), suggesting that changes at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that the p.Cys340Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Supporting, PM5_Supporting. |
| Fundacion Hipercolesterolemia Familiar | RCV000237709 | SCV000607545 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | flagged submission | research |