ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1393T>A (p.Tyr465Asn) (rs730882101)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237809 SCV000295410 likely benign Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000161986 SCV000697196 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1393T>A (p.Tyr465Asn) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/134150 control chromosomes at a frequency of 0.0000149, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). It was reported in FH and early MI patients, however without strong evidence for pathogenicity such as co-segregation. A functional study demonstrated the variant not to have an impact on LDL uptake indicating a neutral outcome, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with L432V (L411V in legacy name) although the phase not well established. Taken together, this variant is classified as VUS until more evidence becomes available.
Invitae RCV001041965 SCV001205619 uncertain significance Familial hypercholesterolemia 2020-04-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 465 of the LDLR protein (p.Tyr465Asn). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs730882101, ExAC 0.003%). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia, including in some individuals with a second variant in LDLR (PMID: 15199436, 25647241, 25487149). ClinVar contains an entry for this variant (Variation ID: 183114). 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. 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.
Color Health, Inc RCV001041965 SCV001353774 uncertain significance Familial hypercholesterolemia 2020-03-20 criteria provided, single submitter clinical testing
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161986 SCV000189561 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237809 SCV000606413 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.