Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
LDLR- |
RCV000231049 | SCV000295507 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-25 | criteria provided, single submitter | literature only | |
Iberoamerican FH Network | RCV000231049 | SCV000748056 | likely pathogenic | Hypercholesterolemia, familial, 1 | 2016-03-01 | criteria provided, single submitter | research | |
Broad Institute Rare Disease Group, |
RCV000231049 | SCV001422782 | uncertain significance | Hypercholesterolemia, familial, 1 | 2020-01-22 | criteria provided, single submitter | curation | The p.Gly529Asp variant in LDLR has been reported in 2 individuals (including 1 Mexican individual) with Familial Hypercholesterolemia (PMID: 21722902, 22998978), and has been identified in 0.005787% (2/34562) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs878854025). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This splice variant is predicted to cause a deletion of an exon and is not predicted to alter the protein reading-frame. The exon deletion is expected to impact the EGF-precursor homology domain (PMID: 21722902). One VUS with a different amino acid change at the same position, p.Gly529Arg, has been reported in association with disease in ClinVar (Variation ID: 183122). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM4, PS4_Supporting (Richards 2015). |
Invitae | RCV001376907 | SCV001574101 | likely pathogenic | Familial hypercholesterolemia | 2021-03-16 | 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. Nucleotide substitutions within 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 disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 21722902, 22998978). ClinVar contains an entry for this variant (Variation ID: 237863). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 529 of the LDLR protein (p.Gly529Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. |
Preventiongenetics, |
RCV003422135 | SCV004107780 | likely pathogenic | LDLR-related condition | 2023-07-31 | criteria provided, single submitter | clinical testing | The LDLR c.1586G>A variant is predicted to result in the amino acid substitution p.Gly529Asp. This variant has been reported in multiple individuals with hypercholesterolemia (Table S1, Pisciotta et al. 2012. PubMed ID: 22998978; Table 2, Vaca et al. 2011. PubMed ID: 21722902). This variant is predicted to abolish the canonical splice donor site by in silico prediction programs (Alamut Visual Plus V1.6.1). However, the use of computer prediction programs is not equivalent to function evidence. This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11224438-G-A). This variant is interpreted as likely pathogenic. |