ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.257_265delTCTGGAGGT (p.Phe86_Arg88del) (rs879254451)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481990 SCV000568519 likely pathogenic not provided 2016-11-21 criteria provided, single submitter clinical testing The c.257_265delTCTGGAGGT likely pathogenic variant (also described as F65_R67del due to alternate nomenclature) in the LDLR gene has been reported previously in at least one German individual with a diagnosis of FH (Geisel et al., 1998; Nauck et al., 2001). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. Although the c.257_265delTCTGGAGGT variant causes the in-frame deletion of three amino acids which does not result in protein truncation, a missense variant at residue Tryptophan 87 has been shown to result in binding defective protein (Leitersdorf et al., 1990). However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000237667 SCV000818131 uncertain significance Familial hypercholesterolemia 2018-06-18 criteria provided, single submitter clinical testing This variant, c.257_265delTCTGGAGGT, results in the deletion of 3 amino acid(s) of the LDLR protein (p.Phe86_Arg88del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in at least one individual affected with familial hypercholesterolemia (PMID: 9676383, 11462246). This variant is also known as delF65-R67 in the literature. ClinVar contains an entry for this variant (Variation ID: 251097). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. The p.Trp87 amino acid residue in LDLR has been determined to be clinically significant (PMID: 2318961, 12553167, 16542394, 8098448). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
LDLR-LOVD, British Heart Foundation RCV000237667 SCV000294559 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only

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