ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.427T>C (p.Cys143Arg) (rs875989901)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237201 SCV000294704 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237201 SCV000322898 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237201 SCV000540715 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing Disrupt disulfide bridge between Cys128 and Cys143.
Fulgent Genetics,Fulgent Genetics RCV000237201 SCV000894166 pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000775039 SCV000909136 likely pathogenic Familial hypercholesterolemia 2018-08-21 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant (also known as p.Cys122Arg in the mature protein) is located in the third LDLR type A repeat of the ligand binding domain of the LDLR protein. Although functional studies have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the ligand binding domain (PMID: 15952897) and is expected to have deleterious impact on the LDLR protein folding and stability. Computational splicing tools suggest that this variant may not impact the RNA splicing. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11462246, 21310417, 22698793, 24627126). In addition, different variants occurring in the same amino acid position (p.Cys143Tyr, p.Cys143Gly) are considered deleterious (Clinvar). Based on available evidence, this variant is classified as Likely Pathogenic.

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