ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.590G>T (p.Cys197Phe) (rs376459828)

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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 RCV000238173 SCV000294807 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000238173 SCV000322904 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles
Fulgent Genetics,Fulgent Genetics RCV000238173 SCV000894169 likely pathogenic Familial hypercholesterolemia 1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001068108 SCV001233198 pathogenic Familial hypercholesterolemia 2020-07-16 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 197 of the LDLR protein (p.Cys197Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs376459828, ExAC 0.01%). This variant has been observed in individuals with clinical features of hypercholesterolemia (PMID: 1301956, 24507775, 20828696, Invitae). ClinVar contains an entry for this variant (Variation ID: 251309). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys197 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23375686, 20809525, 27816806), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238173 SCV000606166 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV001068108 SCV001422744 uncertain significance Familial hypercholesterolemia 2020-01-23 no assertion criteria provided curation The p.Cys197Phe variant in LDLR has been reported in 1 Portuguese and 1 African American individual with familial hypercholesterolemia (PMID: 20828696, 1301956), and has been identified in 0.006% (1/16232) of African chromosomes by the Genome Aggregation Database (gnomAD,; dbSNP rs376459828). This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 251309). In vitro functional studies provide some evidence that the p.Cys197Phe variant may slightly impact protein function (PMID: 1301956). 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. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Cys197Tyr, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 27816806, 14993243, 1301956, 23064986, 21376320, 18096825/Variation ID: 200919). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PS4_supporting, PS3_supporting, PM5_supporting (Richards 2015).

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