ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1026C>G (p.Asp342Glu) (rs780563386)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000237392 SCV000503282 likely benign Familial hypercholesterolemia 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 , family members = 4 unclear co-segregation / Software predictions: Benign
GeneDx RCV000590555 SCV000520996 uncertain significance not provided 2017-01-09 criteria provided, single submitter clinical testing The D342E variant of uncertain significance in the LDLR gene, reported as D321E due to alternate nomenclature, has been identified previously in one African American individual with FH; however, this individual also harbors another variant on the opposite LDLR allele (in trans) which is expected to be pathogenic (Hobbs et al., 1992). The D342E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Although this substitution is located in the EGF-like 1 domain, it occurs at a position that is not conserved. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the D342E variant was not observed in in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Integrated Genetics/Laboratory Corporation of America RCV000590555 SCV000697180 uncertain significance not provided 2016-10-21 criteria provided, single submitter clinical testing Variant summary: The c.1026C>G (p.Asp342Glu) in LDLR gene is a missense change that involves a non-conserved nucleotide and 4/4 in silico tools predict benign outcome. The variant of interest is located within EGF-like functional domain, although the functional impact of this missense change is yet to be studied. The variant is absent from the large control population dataset of ExAC but has been reported in compound heterozygosity with a likely pathogenic variant in affected individual via published reports (Hobbs, 1992). In addition, it was cited as Likely Benign by a reputable database/clinical laboratory and published report (Leigh, 2008). At this time there is not sufficient undeniable evidence to classify this variant with confidence. Taken together, the variant was classified as VUS until more data becomes available.
LDLR-LOVD, British Heart Foundation RCV000237392 SCV000295148 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only

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