ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1012T>G (p.Cys338Gly) (rs879254753)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237730 SCV000295137 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589507 SCV000697179 likely pathogenic Familial hypercholesterolemia 2016-11-02 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1012T>G (p.Cys338Gly) variant, alternatively also known as C317G, involves the alteration of a conserved nucleotide and is located in the epidermal growth factor (EGR) precursor homology domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120874 control chromosomes. The variant has been reported in at least four FH patients in literature including a family where the variant was said to co-segregate with disease (Lombardi_2000, Fard-Esfahani_2005, Donato_2014). This variant is expected to be deleterious as mutations involving Cys residues in this gene are recurrent and may affect folding of the protein (Lombardi_2000, Donato_2014). In addition, multiple reports of variation at LDLR residue p.Cys338 have been reported in FH patients including missense changes of this residue to glycine (Gly), serine (Ser), arginine (Arg), and tyrosine (Tyr), as well as a nonsense change (p.Cys338X), suggesting a notion that this residue is mutational hot-spot. Functional studies have shown that binding, uptake, and degradation of iodinated LDL in skin fibroblasts from a patient homozygous for p.Cys338Tyr variant was <10% of normal (reviewed by Donato_2014). Furthermore, one research institution in ClinVar has classified the variant as likely pathogenic. Taken together, this variant is currently classified as likely pathogenic.
Color Health, Inc RCV000589507 SCV000909151 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000237730 SCV001432586 pathogenic Familial hypercholesterolemia 1 2019-05-11 criteria provided, single submitter research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237730 SCV000606293 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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