ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1003G>A (p.Gly335Ser) (rs544453230)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000215066 SCV000271915 likely pathogenic Homozygous familial hypercholesterolemia 2019-03-20 criteria provided, single submitter clinical testing The p.Gly335Ser variant in LDLR (also described as p.Glu314Ser in the literature) has been reported in at least 12 individuals with hypercholesterolemia: in the heterozygous state in at least 10 individuals, in the double heterozygous state in 1 individual who also had a pathogenic variant in the PCSK9 gene, and in the compound heterozygous state with another pathogenic LDLR variant in a set of identical twins with homozygous familial hypercholesterolemia (HoFH; Hobbs 1992, Wang 2001, Laurie 2004, Bertolini 2013, Retterer 2015, Abul-Husn 2016, Rabacchi 2016, Clinvar Variation ID 183105). It has also been identified in 2 individuals with myocardial infarction (Do 2015, Thomaehlen 2015). In the family with HoFH, this variant segregated with disease (in the compound heterozygous state) in 2 other affected siblings and in the heterozygous state in 2 other affected relatives (Rabacchi 2016). Functional studies provide conflicting evidence on the impact of this variant on the protein (Hobbs 1992, Thormaehlen 2015). Additionally, this variant has been identified in 0.005% (7/128886) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of familial hypercholesterolemia (FH) in the general population. Computational prediction tools and conservation analysis suggest that the p.Gly335Ser variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PP1, PP3, PM2_Supporting.
LDLR-LOVD, British Heart Foundation RCV000238015 SCV000295129 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute,Western University RCV000238015 SCV000484723 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238015 SCV000503276 likely benign Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000238015 SCV000583773 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238015 SCV000599356 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Iberoamerican FH Network RCV000238015 SCV000748093 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001201392 SCV000819690 likely pathogenic Familial hypercholesterolemia 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 335 of the LDLR protein (p.Gly335Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs544453230, ExAC 0.01%). This variant has been observed in several individuals affected with familial hypercholesterolemia (FH) (PMID: 1301956, 23375686, 11668627, 28502510, 28008010, 27765764, 15556094) and individuals with myocardial infarction (PMID: 25647241, 25487149). This variant was shown to segregate with FH in a family that also carried another pathogenic variant in LDLR (PMID: 27578127). It is also known as G314S in the literature. ClinVar contains an entry for this variant (Variation ID: 183105). Experimental studies have shown that this missense change on LDLR activity is inconsistent (PMID: 1301956, 25647241). The observation of one or more missense substitutions at this codon (p.Gly335Val) in affected individuals suggests that this may be a clinically significant residue (PMID: 10735632). 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.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161976 SCV000189551 not provided not provided no assertion provided in vitro
Division of Human Genetics,Children's Hospital of Philadelphia RCV000238015 SCV000536701 likely pathogenic Familial hypercholesterolemia 1 2014-10-31 no assertion criteria provided research
Broad Institute Rare Disease Group,Broad Institute RCV001201392 SCV001422749 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Gly335Ser variant in LDLR has been reported in at least 6 individuals with familial hypercholesterolemia (PMID: 1301956, 11668627, 15556094, 27765764, 27578127, 28008010, 2852510) and has been identified in 0.005431% (7/128886) of European (non-Finnish) chromosomes and 0.005016% (1/19938) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs544453230). This variant has also been reported in ClinVar (PMID: 183105) as likely benign by Centre de Genetique Moleculaire et Chromosomique, as a VUS by the Laboratory for Molecular Medicine, as likely pathogenic by the British Heart Foundation, Roberts Research Institute, Instituto Nacional de Saude Doutor Ricardo Jorge, Iberoamerican FH Network, Invitae, and the Children's Hospital of Philadelphia, and as Pathogenic by U4M - Lille University & CHRU Lille. In vitro functional studies provide some evidence that the p.Gly335Ser variant may not impact protein function (PMID: 25647241). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 4 affected individuals with this variant have an alternative molecular basis for familial hypercholesterolemia , suggesting that this variant may not be pathogenic (PMID: 27578127). In summary, the clinical significance of the p.Gly335Arg variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate, PP3, BP5, BS3_supporting (Richards 2015).

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