ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.401G>T (p.Cys134Phe) (rs879254514)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237376 SCV000294687 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Iberoamerican FH Network RCV000237376 SCV000748130 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Color Health, Inc RCV000775037 SCV000909134 likely pathogenic Familial hypercholesterolemia 2019-03-12 criteria provided, single submitter clinical testing
Invitae RCV000775037 SCV001212401 pathogenic Familial hypercholesterolemia 2020-05-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 134 of the LDLR protein (p.Cys134Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 10978268, 11462246, 18718593). This variant is also known as C113F in the literature. ClinVar contains an entry for this variant (Variation ID: 251204). 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.Cys134 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23375686, 11462246, 25921077, 10735632), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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