Submissions for variant NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln)

dbSNP: rs137943601

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV002227157	SCV002506335	uncertain significance	Hypercholesterolemia, familial, 1	2021-12-16	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1222G>C (p.Glu408Gln) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2 and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PP3 - REVEL = 0.768. It is above 0.75, so PP3 is met.
GeneDx	RCV000413896	SCV000492022	likely pathogenic	not provided	2016-12-02	criteria provided, single submitter	clinical testing	The E408Q variant in the LDLR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E408Q variant was not observed 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. The E408Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same codon (E408K, E408V, E408A) have been reported in the Human Gene Mutation Database in association with hypercholesterolemia (Stenson et al., 2014), supporting the functional importance of this codon. The E408Q variant is a strong candidate for a pathogenic variant however the possibility it may be a rare benign variant cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001299282	SCV001488366	likely pathogenic	Familial hypercholesterolemia	2023-03-23	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 sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 408 of the LDLR protein (p.Glu408Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 373430). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Glu408 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301956, 14974088, 17347910, 19843101, 20236128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Ambry Genetics	RCV004992195	SCV005609340	uncertain significance	Cardiovascular phenotype	2024-10-25	criteria provided, single submitter	clinical testing	The p.E408Q variant (also known as c.1222G>C), located in coding exon 9 of the LDLR gene, results from a G to C substitution at nucleotide position 1222. The glutamic acid at codon 408 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.