ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1393T>A (p.Tyr465Asn) (rs730882101)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237809 SCV000295410 likely benign Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America 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.
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 no assertion criteria provided research

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