ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2251C>T (p.Arg751Trp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV001188886 SCV001356058 uncertain significance Familial hypercholesterolemia 2020-04-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193792 SCV001362903 likely benign not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: LDLR c.2251C>T (p.Arg751Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251320 control chromosomes in gnomAD. c.2251C>T has been reported in the literature in Inuit individuals with high LDL cholesterol but it was also detected at a frequency of 0.14 in Inuit populations from Alaska, Canada and Greenland (Dube_2015). This variant frequency is approximately 108-fold of the estimated maximal expected allele frequency for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism prevalent in populations of Inuit origin. However, given Inuit may be regarded as an isolated population it cannot be excluded that the variant could still be clinically relevant. Following in vitro functional assessment p.R751W was determined to have reduced mean mature LDLR expression and a non-significant reduction in binding ability (Dube_2015). In addition, authors stratified plasma lipoprotein profiles based on p.R751W genotype and showed that the variant was not significantly associated with LDL cholesterol overall. They concluded that the variant was not associated with increased risk of clinically actionable hypercholesterolemia. Co-occurrence with a pathogenic variant has been reported (LDLR c.409G>A, p.Gly137Ser; Internal testing). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.

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