Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000238096 | SCV000295075 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Laboratory for Molecular Medicine, |
RCV000455406 | SCV000539508 | uncertain significance | not specified | 2017-01-24 | criteria provided, single submitter | clinical testing | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in ExAC with a MaxMAF of 0.006%. This region is not conserved and 4 mammals and 1 non-mammal have an Arg at this position. It is predicted benign by all predictive tools. It is present in ClinVar with 1 star and classified as VUS by the British Heart Foundation. It is present in 3 patients with FH. |
Color Diagnostics, |
RCV001185251 | SCV001351424 | uncertain significance | Familial hypercholesterolemia | 2023-02-06 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly293Arg in the mature protein) replaces glycine with arginine at codon 314 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Mendelics | RCV000455406 | SCV002518180 | uncertain significance | not specified | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002372047 | SCV002685014 | uncertain significance | Cardiovascular phenotype | 2024-08-09 | criteria provided, single submitter | clinical testing | The p.G314R variant (also known as c.940G>A), located in coding exon 6 of the LDLR gene, results from a G to A substitution at nucleotide position 940. The glycine at codon 314 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 6 and may have some effect on normal mRNA splicing. This variant (also described as legacy p.G293R) has been reported in hypercholesterolemia cohorts; however, clinical details were limited in many cases (Widhalm K et al. J Inherit Metab Dis, 2007 Apr;30:239-47; Durst R et al. Atherosclerosis, 2017 02;257:55-63; Futema M et al. Atherosclerosis, 2017 05;260:47-55; Turkyilmaz A et al. Metab Syndr Relat Disord, 2021 08;19:340-346). Limited functional analyses suggested no significant impact (Thormaehlen AS et al. PLoS Genet, 2015 Feb;11:e1004855). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is not well conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
Fulgent Genetics, |
RCV000238096 | SCV002792252 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-10-26 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001185251 | SCV003259699 | uncertain significance | Familial hypercholesterolemia | 2022-07-30 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 314 of the LDLR protein (p.Gly314Arg). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is present in population databases (rs72658858, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 17347910, 28104544, 28349888). This variant is also known as G293R. ClinVar contains an entry for this variant (Variation ID: 183102). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000455406 | SCV003934616 | uncertain significance | not specified | 2023-05-11 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.940G>A (p.Gly314Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. As the variant affects the last conserved nucleotide of exon 6 adjacent to the intron 6 splice donor site, 4/4 computational tools predict a slight weakening of the canonical 5'-splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 250802 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.940G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (example, Widhalm_2007, Durst_2017, Futema_2017, Rimbert_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28104544, 28349888, 35047021, 17347910). Eight 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Center for Genomic Medicine, |
RCV000238096 | SCV004806637 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-03-26 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV000238096 | SCV004820235 | uncertain significance | Hypercholesterolemia, familial, 1 | 2024-08-06 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly293Arg in the mature protein) replaces glycine with arginine at codon 314 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown the mutant protein to show normal protein maturation and plasma membrane localization (Khalid Jawabri 2020, dissertation, United Arab Emirates University). This variant has been reported in several individuals affected with premature atherosclerosis and/or familial hypercholesterolemia in the literature (PMID: 17347910, 33794673). This variant has been identified in 13/282176 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Breakthrough Genomics, |
RCV000161973 | SCV005192581 | uncertain significance | not provided | criteria provided, single submitter | not provided | ||
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000161973 | SCV005625866 | uncertain significance | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | The LDLR c.940G>A (p.Gly314Arg) variant has been reported in the published literature in individuals with hypercholesterolemia (PMIDs: 33794673 (2021), 35047021 (2021), 28349888 (2017), 28104544 (2017), 17347910 (2007)). A functional study indicated this variant has neutral effect on cellular LDL-uptake efficiency (PMID: 25647241 (2015)). The frequency of this variant in the general population, 0.00007 (9/128680 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper LDLR mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. |
Dept. |
RCV000161973 | SCV000189548 | not provided | not provided | no assertion provided | in vitro | ||
Natera, |
RCV001185251 | SCV001460260 | uncertain significance | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing |