ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1823C>T (p.Pro608Leu)

dbSNP: rs879255035
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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 RCV000238385 SCV000295680 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV003581632 SCV004298372 pathogenic Familial hypercholesterolemia 2023-01-14 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 608 of the LDLR protein (p.Pro608Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro608 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9544745, 9852677), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. ClinVar contains an entry for this variant (Variation ID: 252051). This variant is also known as p.P587L. This missense change has been observed in individuals with autosomal dominant hypercholesterolemia (PMID: 11313767, 11851376, 16250003, 23054246; Invitae). This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health RCV003581632 SCV004359045 likely pathogenic Familial hypercholesterolemia 2021-11-26 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 608 in the LDLR type B repeat 5 (aa 572-615) in the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro587Leu in the mature protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple heterozygous individuals affected with familial hypercholesterolemia (PMID: 11313767, 11851376, 16250003, 18700895, 19318025, 19837725). This variant has also been observed in the compound heterozygous state with a pathogenic truncation in the LDLR gene in a 22-year old individual affected with homozygous familial hypercholesterolemia (Revaiah et al, https://doi.org/10.1016/j.jccase.2021.05.011). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Other missense variants occurring at the same position have been described in individuals with familial hypercholesterolemia: p.Pro608Ser (ClinVar variation ID: 252049), p.Pro608Thr (ClinVar variation ID: 252048), p.Pro608Arg (ClinVar variation ID: 252050). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238385 SCV000606524 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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