ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1166C>T (p.Thr389Met)

gnomAD frequency: 0.00002  dbSNP: rs149227308
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237987 SCV000295252 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237987 SCV000503307 uncertain significance Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting
Color Diagnostics, LLC DBA Color Health RCV001181606 SCV001346785 uncertain significance Familial hypercholesterolemia 2022-12-08 criteria provided, single submitter clinical testing This missense variant (also known as p.Thr368Met in the mature protein) replaces threonine with methionine at codon 389 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). To our knowledge, functional studies have not been reported for this variant. This variant has been identified in at least 4 individuals affected with familial hypercholesterolemia (PMID: 17196209, 20091938, 23375686, 28161202, Color Health internal data, ClinVar SCV001538685.2). In one family, this variant was reported in two siblings affected with familial hypercholesterolemia (PMID: 17196209). This variant has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149) and in an individual affected with coronary artery disease (PMID: 27050191). This variant has been identified in 5/250884 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.
Invitae RCV001181606 SCV001538685 pathogenic Familial hypercholesterolemia 2023-11-29 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 389 of the LDLR protein (p.Thr389Met). This variant is present in population databases (rs149227308, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 17196209, 23375686; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 161283). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics RCV002223790 SCV002502047 uncertain significance not provided 2022-02-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002326857 SCV002627462 uncertain significance Cardiovascular phenotype 2021-05-25 criteria provided, single submitter clinical testing The p.T389M variant (also known as c.1166C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at nucleotide position 1166. The threonine at codon 389 is replaced by methionine, an amino acid with similar properties. This variant (also referred to as p.T368M) has been detected in a pediatric proband with hypercholesterolemia, and segregated with disease in two relatives (Campagna F et al. Atherosclerosis, 2008 Jan;196:356-364). This variant has been detected in additional hypercholesterolemia cohorts and an early-onset myocardial infarction cohort; however, details were limited and case reports may overlap (Noto D et al. Pediatr Res, 2010 Feb;67:200-4; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Do R et al. Nature, 2015 Feb;518:102-6). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003488400 SCV004241553 uncertain significance not specified 2023-12-21 criteria provided, single submitter clinical testing Variant summary: LDLR c.1166C>T (p.Thr389Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250884 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1166C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia, early-onset myocardial infarction and participants receiving genetic testing for lipid diseases (examples, Bertolini_2013, Campagna_2008, Do_2015, Dron_2020, Grzymski_2020, Noto_ 2010). However detailed clinical or genetic formation were not always provided for independent analysis (examples, Bertolini_2013, Do_2015, Dron_2020). 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: 23375686, 17196209, 25487149, 32041611, 32719484, 20091938). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=5; Likely pathogenic/Pathogenic, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington RCV002051676 SCV000190304 uncertain significance Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237987 SCV000606340 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV001181606 SCV002086406 uncertain significance Familial hypercholesterolemia 2020-06-11 no assertion criteria provided clinical testing

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