ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) (rs748554592)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238583 SCV000295319 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000238583 SCV000484747 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Color Health, Inc RCV000775061 SCV000909162 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000775061 SCV001360702 pathogenic Familial hypercholesterolemia 2019-07-08 criteria provided, single submitter clinical testing Variant summary: LDLR c.1241T>G (p.Leu414Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251172 control chromosomes. c.1241T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Mak_1998, Kondkar_2007, Chiou_2017, Chan_2018, Pek_2018), predominantly in individuals from Asian origin. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cite variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238583 SCV001432554 pathogenic Familial hypercholesterolemia 1 2019-03-13 criteria provided, single submitter research
Invitae RCV000775061 SCV001575511 likely pathogenic Familial hypercholesterolemia 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 414 of the LDLR protein (p.Leu414Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is present in population databases (rs748554592, ExAC 0.01%). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 9452118, 27765764). This variant is also known as L393R in the literature. ClinVar contains an entry for this variant (Variation ID: 251747). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238583 SCV000606369 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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