ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1981C>G (p.Pro661Ala)

dbSNP: rs1182317785
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV003229003 SCV003926164 likely pathogenic not provided 2022-10-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect with 50% reduction of LDL uptake and catabolism compared to wild type (Gomez et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31689621, Gomez2018[Article])
Invitae RCV003741244 SCV004535400 uncertain significance Familial hypercholesterolemia 2023-12-10 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 661 of the LDLR protein (p.Pro661Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 31689621). ClinVar contains an entry for this variant (Variation ID: 810849). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. Experimental studies have shown that this missense change affects LDLR function (PMID: 31689621). 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.
Fundacion Favaloro, PRICAI RCV001000104 SCV001156525 likely pathogenic Hypercholesterolemia, familial, 1 2019-05-29 no assertion criteria provided research

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