ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.409G>A (p.Gly137Ser) (rs730882082)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237389 SCV000294690 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000237389 SCV000540731 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000161956 SCV001246002 likely pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193789 SCV001362900 likely pathogenic Familial hypercholesterolemia 2019-11-25 criteria provided, single submitter clinical testing Variant summary: LDLR c.409G>A (p.Gly137Ser) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of 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 1.6e-05 in 251184 control chromosomes (gnomAD). c.409G>A has been reported in the literature in individuals affected with hypercholesterolemia (Cameron_2012, Damgaard_2005, Dube_2015). These data indicate that the variant is likely to be associated with disease. One study (Dube_2015) determined the frequency of the variant in Inuit general population from Alaska, Canada and Greenland to be relatively high at 10%. Authors stratified plasma lipoprotein profiles according to LDLR p.G137S genotype and determined that carriers had approximately a 3-fold increased risk of hypercholesterolemia, but did not have classical familial hypercholesterolemia. They finally concluded that the variant is a common, dysfunctional variant in Inuit that is strongly associated with a large LDL cholesterol-raising effect, although not causing classical FH. One functional study demonstrated the variant to confer no effect on LDL uptake (Thormaehlen_2015) while another study determined it caused a significant 61% reduction in LDL binding ability (Dube_2015). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161956 SCV000189531 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237389 SCV000606108 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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