Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000238415 | SCV001960939 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-06-18 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.2101G>A (p.Gly701Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1_Moderate and PP3) 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: PP1_moderate - Variant segregates with FH phenotype in 4 informative meioses in 2 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,754. |
LDLR- |
RCV000238415 | SCV000295875 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Molecular Genetics Laboratory, |
RCV000238415 | SCV000540860 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-11-05 | criteria provided, single submitter | clinical testing | |
Fundacion Hipercolesterolemia Familiar | RCV000238415 | SCV000607677 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000162008 | SCV000697222 | uncertain significance | not provided | 2017-06-07 | criteria provided, single submitter | clinical testing | Variant summary: The LDLR c.2101G>A (p.Gly701Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large and broad control population from ExAC in 17/137956 control chromosomes at a frequency of 0.0001232, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been reported in patients with hypercholesterolemia, coronary artery disease and/or myocardial infarction (Fouchier _2005, Duskova _2011, Thormaehlen_2015, Khera_2016) without strong evidence for causality. In two case-control studies, this variant was not significantly more enriched in patients with coronary artery disease and/or myocardial infarction than in controls (Thormaehlen_2015, Khera_2016). Based on LDLR uptake and complementation assay, one in vitro study has concluded that its pathogenicity or functional outcome is unclear (Thormaehlen _2015). There are conflicting reports of classification on this variant in ClinVar, likely pathogenic as well as likely benign (both in 2016). Taken together, this variant is currently classified as Variant of Unknown Significance. |
Mendelics | RCV000238415 | SCV001140985 | uncertain significance | Hypercholesterolemia, familial, 1 | 2023-06-02 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001181781 | SCV001347005 | uncertain significance | Familial hypercholesterolemia | 2023-03-15 | criteria provided, single submitter | clinical testing | This missense variant (also known as p.Gly680Ser in the mature protein) replaces glycine with serine at codon 701 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 this variant to cause a partial reduction in LDL uptake activity of the LDLR protein (PMID: 25647241). This variant has not shown significant association with increased LDL-C levels, coronary artery disease, or myocardial infarction (PMID: 22390909, 25647241). This variant has been identified in 25/282378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is no indication that this variant is disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002415707 | SCV002724555 | uncertain significance | Cardiovascular phenotype | 2023-06-09 | criteria provided, single submitter | clinical testing | The p.G701S variant (also known as c.2101G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 2101. The glycine at codon 701 is replaced by serine, an amino acid with similar properties. This variant has been detected in individuals from familial hypercholesterolemia, familial combined hyperlipidemia, and early onset myocardial infarction cohorts; however, in most cases clinical details were limited, and p.G701S was also seen in reportedly unaffected controls (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Civeira F et al. J. Am. Coll. Cardiol., 2008 Nov;52:1546-53; Dušková L et al. Atherosclerosis, 2011 May;216:139-45; Do R et al. Nature, 2015 Feb;518:102-6; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). The results of limited functional studies were inconclusive (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV000238415 | SCV002794037 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-10-20 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001181781 | SCV002943680 | uncertain significance | Familial hypercholesterolemia | 2022-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 701 of the LDLR protein (p.Gly701Ser). This variant is present in population databases (rs368838866, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia or referred for genetic testing (PMID: 16250003, 19007590, 19318025, 21310417, 22390909, 25487149). ClinVar contains an entry for this variant (Variation ID: 183130). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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. |
Dept. |
RCV000162008 | SCV000189583 | not provided | not provided | no assertion provided | in vitro | ||
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000238415 | SCV000606599 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Diagnostic Laboratory, |
RCV000238415 | SCV000733828 | likely benign | Hypercholesterolemia, familial, 1 | no assertion criteria provided | clinical testing | ||
Natera, |
RCV001181781 | SCV001461327 | uncertain significance | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing | |
Clinical Genetics, |
RCV000162008 | SCV001917981 | likely benign | not provided | no assertion criteria provided | clinical testing |