ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1060G>A (p.Asp354Asn)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003074993 SCV003461827 likely pathogenic Familial hypercholesterolemia 2022-07-03 criteria provided, single submitter clinical testing 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 29353225, 32331935; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 354 of the LDLR protein (p.Asp354Asn). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon.

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