ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2389G>T (p.Val797Leu) (rs750518671)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237754 SCV000295968 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000237754 SCV000323010 uncertain significance Familial hypercholesterolemia 2016-03-01 criteria provided, single submitter research 0/150 non-FH alleles
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237754 SCV000583946 pathogenic Familial hypercholesterolemia 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000808288 SCV000948390 pathogenic Familial hypercholesterolemias 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 797 of the LDLR protein (p.Val797Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant also falls at the last nucleotide of exon 16 of the LDLR coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 19411563) and has been observed in an individual affected wit familial hypercholesterolemia (PMID: 10735632). This variant is also known as V776L in the literature. ClinVar contains an entry for this variant (Variation ID: 252298). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change results in skipping of exon 16 (PMID: 19411563). A different variant affecting this nucleotide (c.2389G>T) has been determined to be pathogenic (PMID: 23375686, 19446849, 22698793, 22859806, 20145306, 9763532). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237754 SCV000606635 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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