Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000211598 | SCV001960949 | uncertain significance | Hypercholesterolemia, familial, 1 | 2021-06-23 | reviewed by expert panel | curation | The NM_000527.5(LDLR):c.185C>T (p.Thr62Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP1) 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 - variant segregates with FH phenotype in 3 informative meiosis in 2 families from different labs (Laboratory of Genetics and Molecular Cardiology and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). |
Invitae | RCV000775024 | SCV000285020 | uncertain significance | Familial hypercholesterolemia | 2022-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 62 of the LDLR protein (p.Thr62Met). This variant is present in population databases (rs376207800, gnomAD 0.02%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 16250003, 19446849, 19717150, 25606447, 26892515, 33303402). This variant is also known as p.Thr41Met. ClinVar contains an entry for this variant (Variation ID: 161273). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. |
LDLR- |
RCV000211598 | SCV000294497 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | research | |
Cardiovascular Research Group, |
RCV000211598 | SCV000322877 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | 0/190 non-FH alleles |
Centre de Génétique Moléculaire et Chromosomique, |
RCV000211598 | SCV000503106 | likely benign | Hypercholesterolemia, familial, 1 | 2016-12-16 | criteria provided, single submitter | clinical testing | subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging |
Laboratory for Molecular Medicine, |
RCV000454406 | SCV000539515 | uncertain significance | not specified | 2016-03-31 | 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: Identified in equal number of cases and controls; ExAC: 3/164246 South Asian; ClinVar: 1 VUS |
Laboratory of Genetics and Molecular Cardiology, |
RCV000211598 | SCV000588487 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Fundacion Hipercolesterolemia Familiar | RCV000211598 | SCV000607423 | uncertain significance | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Color Diagnostics, |
RCV000775024 | SCV000909121 | likely benign | Familial hypercholesterolemia | 2022-10-11 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002408657 | SCV002722204 | uncertain significance | Cardiovascular phenotype | 2022-12-06 | criteria provided, single submitter | clinical testing | The p.T62M variant (also known as c.185C>T), located in coding exon 2 of the LDLR gene, results from a C to T substitution at nucleotide position 185. The threonine at codon 62 is replaced by methionine, an amino acid with similar properties. This variant has been reported in hypercholesterolemia cohorts but limited clinical information was provided (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Leigh SE et al. Ann. Hum. Genet., 2008 Jul;72:485-98; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sharifi M et al. Metab. Clin. Exp., 2016 Mar;65:48-53). This variant has also been detected in exome cohorts and healthy controls with limited cardiovascular history (Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Do R et al. Nature, 2015 Feb;518:102-6; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Khera AV et al. J. Am. Coll. Cardiol., 2016 06;67:2578-89). Limited functional studies have suggested no significant impact on LDLR expression, binding, or uptake (Thormaehlen AS et al. PLoS Genet., 2015 Feb;11:e1004855; Benito-Vicente A et al. Sci Rep, 2018 Nov;8:16614). This amino acid position is 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, |
RCV000211598 | SCV002806748 | uncertain significance | Hypercholesterolemia, familial, 1 | 2022-02-15 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000454406 | SCV004241787 | uncertain significance | not specified | 2023-12-04 | criteria provided, single submitter | clinical testing | Variant summary: LDLR c.185C>T (p.Thr62Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250804 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.00012 vs 0.0013), allowing no conclusion about variant significance. c.185C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Fouchier_2005, Guardamagna_2009, Junyent_2010, Cymbron_2014, Sharifi_2016, Gill_2020). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. Functional studies report experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Thormaehlen_2015, Benito-Vicente_2018, Graca_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30413722, 25606447, 16250003, 33303402, 35568682, 19446849, 19717150, 34456049, 26892515, 25647241). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=11) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |
Dept. |
RCV000161951 | SCV000189526 | not provided | not provided | no assertion provided | in vitro | ||
CSER _CC_NCGL, |
RCV002051666 | SCV000190293 | uncertain significance | Hypercholesterolemia | 2014-06-01 | no assertion criteria provided | research | |
Cardiovascular Genetics Laboratory, |
RCV000211598 | SCV000268536 | uncertain significance | Hypercholesterolemia, familial, 1 | 2015-05-08 | no assertion criteria provided | clinical testing | |
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, |
RCV000211598 | SCV000606034 | pathogenic | Hypercholesterolemia, familial, 1 | no assertion criteria provided | research |