ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1019G>A (p.Cys340Tyr) (rs755757866)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000775249 SCV000909507 likely pathogenic Familial hypercholesterolemias 2018-10-04 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Cys319Tyr in the mature protein) is located in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed for this variant, it changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals diagnosed with familial hypercholesterolemia (PMID: 15241806, 27824480). Based on available evidence this variant is classified as Likely Pathogenic.
Fundacion Hipercolesterolemia Familiar RCV000237709 SCV000607545 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
LDLR-LOVD, British Heart Foundation RCV000237709 SCV000295143 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237709 SCV000540782 likely pathogenic Familial hypercholesterolemia 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys340 and Cys352.

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