ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys) (rs368708058)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238106 SCV000295340 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Color Health, Inc RCV001526181 SCV001736482 likely pathogenic Familial hypercholesterolemia 2020-11-11 criteria provided, single submitter clinical testing This missense variant (also known as p.Asn407Lys in the mature protein) replaces asparagine with lysine at codon 428 in LDLR type B repeat 1 (aa 397-438) of EGF precursor homology domain of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypercholesterolemia in diverse ethnic populations (PMID: 11005141, 11668640, 11845603, 11857755, 14508510, 15556094, 21382890). This variant has been observed in compound heterozygous state with a known pathogenic variant in a South African Jewish individual affected with severe familial hypercholesterolemia, coronary heart disease and tendon xanthomata (Callis 2000 dissertation, University of the Orange Free State). Heterozygous relatives of this proband were also affected with hypercholesterolemia. This variant has been detected in over 30 Dutch individuals showing modest severity of hypercholesterolemia with mean LDL-C levels in the 75-88th percentile according to the Dutch lipid clinic network criteria (Hartgers 2020 dissertation, Univ. of Amsterdam). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238106 SCV000606380 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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