Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000210245 | SCV002568110 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-05-30 | reviewed by expert panel | curation | NM_000527.5(LDLR):c.2252G>A (p.Arg751Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PS4_supporting and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001602 (0.01602%) in African/African American exomes+genomes (gnomAD v2.1.1). PS4_supporting - Variant meets PM2 and is identified in 2 unrelated index cases (1 case published in PMID: 16250003 (Fouchier et al., 2005), Netherlands; 1 case published in PMID: 16159606 (Graham et al., 2005), United Kingdom). PP4 - Variant meets PM2. PMID: 16159606 - 1 case who fulfills Simon-Broome criteria for FH. |
CSER _CC_NCGL, |
RCV002051679 | SCV000190308 | uncertain significance | Hypercholesterolemia | 2014-06-01 | criteria provided, single submitter | research | Low GERP score may suggest that this variant may belong in a lower pathogenicity class |
Cardiovascular Biomarker Research Laboratory, |
RCV000210245 | SCV000266313 | uncertain significance | Hypercholesterolemia, familial, 1 | 2015-08-31 | criteria provided, single submitter | research | MAF =<0.3%, LDL-C >=160 mg/dL |
LDLR- |
RCV000210245 | SCV000295926 | likely benign | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Invitae | RCV000815637 | SCV000956098 | uncertain significance | Familial hypercholesterolemia | 2022-08-22 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 751 of the LDLR protein (p.Arg751Gln). This variant is present in population databases (rs200142970, gnomAD 0.02%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16159606, 16250003). ClinVar contains an entry for this variant (Variation ID: 161286). 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 glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
Color Diagnostics, |
RCV000815637 | SCV001344869 | uncertain significance | Familial hypercholesterolemia | 2023-01-18 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 751 of the LDLR protein. This variant is also known as p.Arg730Gln in the mature 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least four individuals affected with familial hypercholesterolemia (PMID: 16159606, 16250003, 28145427, 33955087). This variant has also been identified in 22/282676 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. |
Gene |
RCV000996761 | SCV001785178 | uncertain significance | not provided | 2019-06-06 | criteria provided, single submitter | clinical testing | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28145427, 16159606, 16250003, 25637381, 18325082) |
Ambry Genetics | RCV002444608 | SCV002735235 | likely benign | Cardiovascular phenotype | 2022-05-03 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000210245 | SCV000606620 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research | ||
Natera, |
RCV000815637 | SCV001461330 | uncertain significance | Familial hypercholesterolemia | 2020-09-16 | no assertion criteria provided | clinical testing |