Submissions for variant NM_000527.5(LDLR):c.1026C>G (p.Asp342Glu) (rs780563386)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237392	SCV000295148	likely benign	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
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 1	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.
Invitae	RCV001064785	SCV001229705	uncertain significance	Familial hypercholesterolemia	2019-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with glutamic acid at codon 342 of the LDLR protein (p.Asp342Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with familial hypercholesterolemia (PMID: 1301956). This variant is also known as D321E and FH New York-1 in the literature. ClinVar contains an entry for this variant (Variation ID: 251604). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.