ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1898G>T (p.Arg633Leu)

dbSNP: rs754536745
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237353 SCV000295747 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174944 SCV001338397 likely pathogenic Familial hypercholesterolemia 2020-02-03 criteria provided, single submitter clinical testing Variant summary: LDLR c.1898G>T (p.Arg633Leu) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). c.1898G>T has been reported in the literature in multiple Dutch individuals affected with Familial Hypercholesterolemia (FH) (e.g. Fouchier_2005, Huijgen_2010, Huijgen_2012, van de rGraaf_2011, Kusters_2013). The JoJoGenetics database reports the variant in 41 patients known in the Netherlands (status June 2019), without providing further information. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other missense substitutions affecting the same amino acid residue (i.e. p.Arg633Cys, p.Arg633His) have been reported to be deleterious (internal testing and ClinVar), suggesting that the Arg633 is important for protein function. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000237353 SCV000606554 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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