ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

dbSNP: rs875989914
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211597 SCV000268596 pathogenic Hypercholesterolemia, familial, 1 2022-04-05 criteria provided, single submitter clinical testing LDLR p.Arg350Pro (originally Arg329Pro, FH Alghero) missense variant has previously been identified in multiple cohorts of familial hypercholesterolemia patients. In vitro studies demonstrated that LDLR p.Arg350Pro affected protein folding and surface expression, resulting in decreased LDL-receptor activity (PMID: 15100232, 9026534).
LDLR-LOVD, British Heart Foundation RCV000211597 SCV000295162 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV001183695 SCV000627011 likely pathogenic Familial hypercholesterolemia 2021-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 350 of the LDLR protein (p.Arg350Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9026534, 19837725; Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226343). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LDLR function (PMID: 15100232). This variant disrupts the p.Arg350 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 31106925), which suggests that this may be a clinically significant amino acid residue. 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.
Color Health, Inc RCV001183695 SCV001349491 likely pathogenic Familial hypercholesterolemia 2020-11-17 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg329Pro in the mature protein) replaces arginine with proline at codon 350 in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Experimental functional studies have shown that this variant causes LDLR protein misfolding and significant reduction in protein activity (PMID: 9026534, 15100232). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has also been reported in compound heterozygosity with a pathogenic variant p.Cys248Tyr in an individual affected with familial hypercholesterolemia (PMID: 9026534). The proband's affected sister was also compound heterozygous. The proband's affected father was heterozygous for this variant, and the proband's affected mother was heterozygous for p.Cys248Tyr (PMID: 9026534). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been shown to disrupt LDLR function and demonstrated to segregate with disease in a family study. Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV002259322 SCV002538757 likely pathogenic not provided 2022-06-20 criteria provided, single submitter clinical testing Also known as p.R329P; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant results in protein misfolding and reduced cell-surface expression compared to the wild-type protein (Boswell et al., 2004) as well as results in impaired interaction with PCSK9 binding (Gu et al., 2013); This variant is associated with the following publications: (PMID: 17094996, 31106925, 9026534, 24103783, 19837725, 15556093, 11435110, 32719484, 15100232, 22883975)

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