ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1966C>A (p.His656Asn) (rs762815611)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237688 SCV000322993 benign Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/200 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237688 SCV000503441 likely pathogenic Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 5 with co-segregation / previously described in association with FH
Fundacion Hipercolesterolemia Familiar RCV000237688 SCV000607659 benign Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research
LDLR-LOVD, British Heart Foundation RCV000237688 SCV000295782 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237688 SCV000606564 pathogenic Familial hypercholesterolemia no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786344 SCV000925122 likely pathogenic not provided 2016-08-16 no assertion criteria provided provider interpretation The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB and PCSK9. Results showed that the following variant was identified: p.His656Asn (c.1966C>A) in the LDLR gene (NM_000527.4) The lab classifies this variant as likely pathogenic. Given sufficient case data and functional studies, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least five unrelated cases of familial hypercholesterolemia (not including this patient's family). There is strong case data. Mozas P et al. Hum Mutat. 2004:24(2):187, reported this variant in one individual and predicted that the basic to neurtral amino acid change could be expected to alter the conformation of the protein and, therefore, to prevent the transport to the Golgi apparatus of the misfolded LDLR. This article reports the variant as p.H635N Damgaard D et al. Atherosclerosis. 2005;180(1):155-60 reported this variant as novel in two individuals of a large FH cohort. They did not provide additional phenotype details. This article reports the variant as p.H635N van der Graaf A et al. Circulation. 2011;123(11):1167-73 reported this variant in a pediatric individual who presented with familial hypercholesterolemia. They did not provide additional phenotypic details. Bertolini et al. Atherosclerosis. 2013 Apr;227(2):342-8 reported this variant in their cohort of FH patients, but supplemental figures are unavailable. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The histadine at codon 656 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at the same codon (p.H635Q). A study using surface plasmon resonance spectroscopy showed that this variant results in altered binding for substrate at low pH (Lo Surdo P et al. EMBO Rep. 2011;12(12):1300-5). In addition, another alteration affecting this amino acid (p.H656Q, c.1968C>G) has been reported in association with hypercholesterolemia (Descamps OS et al. Eur J Clin Invest. 2001;31(11):958-65 (reported as p.H635Q)). There are two individuals with variation at codon 656 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 16, 2016).

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