Submissions for variant NM_000527.5(LDLR):c.504C>A (p.Asp168Glu)

gnomAD frequency: 0.00001  dbSNP: rs777321035

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238338	SCV000294750	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238338	SCV000484741	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238374	SCV001411180	likely pathogenic	Familial hypercholesterolemia	2019-08-19	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Asp168 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8462973, 28104544, 20828696, 16250003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15823276, 27765764, Invitae). ClinVar contains an entry for this variant (Variation ID: 251261). This variant is also described as Asp147Glu (D147E) in the literature. This variant is present in population databases (rs777321035, ExAC 0.009%). This sequence change replaces aspartic acid with glutamic acid at codon 168 of the LDLR protein (p.Asp168Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000238338	SCV001423093	uncertain significance	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Asp168Glu variant in LDLR has been reported in one Turkish individual in the homozygous state and in one individual in the heterozygous state with Familial Hypercholesterolemia (PMID: 15823276, 27765764), and has been identified in 0.005782% (2/34592) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs777321035). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 251261). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Asp168Asn and p.Asp168His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 8462973, 28966723, 8882879, 28104544, 16250003, 20828696, 27784735, 25647241, 25545329, 16389549, 28379029, 16205024, 19007590, 15556094, 9259195, 22859806, 9678702 /Variation ID: 183136, 251258). The phenotype of a 5 year old Turkish individual homozygous for this variant is highly specific for Familial Hypercholesterolemia based on tendon xanthoma, arcus cornia, and cholesterol levels consistent with disease (PMID: 15823276). Homozygotes with pathogenic variants in this gene are known to have a more severe and earlier onset phenotype than heterozygotes. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM5, PP4, PS4_Supporting, PP3 (Richards 2015).
GeneDx	RCV004719785	SCV005325295	likely pathogenic	not provided	2024-03-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D147E); This variant is associated with the following publications: (PMID: 33303402, 32770674, 15823276)