ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1946C>T (p.Pro649Leu)

dbSNP: rs879255081
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237373 SCV000295764 uncertain significance 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 RCV000237373 SCV000503435 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 /FH-UK/software prediction damaging
Fundacion Hipercolesterolemia Familiar RCV000237373 SCV000607656 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330605 SCV004037622 likely pathogenic Familial hypercholesterolemia 2023-08-28 criteria provided, single submitter clinical testing Variant summary: LDLR c.1946C>T (p.Pro649Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). c.1946C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Day_1997, Tosi_2007, Du_2022, Sustar_2022). These data indicate that the variant is likely to be associated with disease. 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: 9259195, 36325061, 35913489, 17094996). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS or likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV003330605 SCV004297869 likely pathogenic Familial hypercholesterolemia 2023-02-28 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9259195). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 649 of the LDLR protein (p.Pro649Leu). This variant is not present in population databases (gnomAD no frequency). This variant is also known as P628L. ClinVar contains an entry for this variant (Variation ID: 252122). 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. This variant disrupts the p.Pro649 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20809525; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237373 SCV000606560 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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