ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1049G>C (p.Arg350Pro) (rs875989914)

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Total submissions: 3
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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 Familial hypercholesterolemia 2008-06-05 no assertion criteria provided clinical testing
Invitae RCV000211597 SCV000627011 uncertain significance Familial hypercholesterolemia 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.
LDLR-LOVD, British Heart Foundation RCV000211597 SCV000295162 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only

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