ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1322T>C (p.Ile441Thr) (rs879254862)

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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 RCV000237607 SCV000295362 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237607 SCV000322942 pathogenic Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/100 healthy control individuals
Color RCV000775063 SCV000909164 pathogenic Familial hypercholesterolemias 2018-07-09 criteria provided, single submitter clinical testing Pathogenic variant based on current evidence: This missense variant (also known as p.Ile420Thr in the mature protein) is located in the LDLR type B repeat 2 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. Experimental studies in CHO cells have shown that this variant causes a near complete loss of LDLR activity (~10% of normal) with retention in the endoplasmic reticulum as the precursor form (PMID: 25741862). This variant has been shown to segregate with hypercholesterolemia in 9 of 10 affected individuals from four different Portuguese families (PMID: 25741862). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Different missense variants at the same codon (p.Ile441Asn and p.Ile 441Met) are considered to be disease-causing. Based on available evidence, this variant is classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237607 SCV000606392 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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