ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.683A>C (p.Glu228Ala)

dbSNP: rs879254642
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237123 SCV000294908 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000421699 SCV000516953 pathogenic not provided 2015-05-16 criteria provided, single submitter clinical testing The E228A substitution in the LDLR gene has been previously reported in the homozygous state in an individualwith hypercholesterolemia (Liu et al, 2004). Additional missense variants at the same codon (E228Q andE228K), and nearby residues (D227E and C231G) have been reported in the Human Gene Mutation Databasein association with hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. The E228A variant was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The E228A variant is a non-conservative amino acid substitution, which is likelyto impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.This substitution occurs at a position that is conserved across species. In silico analysis predicts this variantis probably damaging to the protein structure/function. Therefore, we interpret the E228A variant as pathogenic.

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