ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1966C>A (p.His656Asn) (rs762815611)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237688 SCV000295782 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237688 SCV000322993 benign Familial hypercholesterolemia 1 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 1 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 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001242724 SCV001415830 likely pathogenic Familial hypercholesterolemia 2019-10-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with asparagine at codon 656 of the LDLR protein (p.His656Asn). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and asparagine. This variant is present in population databases (rs762815611, ExAC 0.003%). This variant has been observed in several individuals affected with familial hypercholesterolemia (FH) (PMID: 15241806, 15823288, 20828696, 21382890, 23375686). This variant is also known as H635N in the literature. ClinVar contains an entry for this variant (Variation ID: 252136). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.His656 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11737238), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000237688 SCV001429019 uncertain significance Familial hypercholesterolemia 1 2019-07-09 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237688 SCV000606564 pathogenic Familial hypercholesterolemia 1 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 (, 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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