ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro) (rs875989914)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211597 SCV000295162 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000211597 SCV000627011 uncertain significance Familial hypercholesterolemia 1 2017-03-03 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 variant has been reported in the literature in the heterozygous state in two siblings affected with hypercholesterolemia in combination with a likely pathogenic variant in the other chromosome (PMID: 9026534). It has also been reported in the heterozygous state in an individual affected with hypercholesterolemia (PMID: 19837725). ClinVar contains an entry for this variant (Variation ID: 226343). Experimental studies have shown that this missense change causes LDLR protein misfolding and reduced expression at the cell surface (PMID: 15100232). In summary, this variant is a rare missense change that has been shown to affect protein function and it has been reported in affected individuals. However, additional genetic and/or functional data is necessary to classify this variant conclusively. For these reasons, it has been classified as a Variant of Uncertain Significance.
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.
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211597 SCV000268596 pathogenic Familial hypercholesterolemia 1 2008-06-05 no assertion criteria provided clinical testing

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