ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.2113G>C (p.Ala705Pro) (rs193922570)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000030132 SCV000733829 pathogenic Familial hypercholesterolemia no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722114 SCV000052787 pathogenic Familial hypercholesterolemias 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The c.2113G>C (p.Ala705Pro) in LDLR gene is a missense variant involves a highly conserved nucleotide and 2/4 in silico tools (SNPsandGO not captured here due to low reliability index value) predict deleterious outcome. However, no functional studies supporting these predictions were published at the time of evaluation. The c.2113G>C is present in the control population dataset of gnomAD at a low frequency of 0.000004 (1/245716 chromosomes tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0012, suggesting that it is not a common polymorphism. The variant has been reported in multiple affected individuals with FH, including one patient, who carried R3500Q in APOB with lipid profile suggestive of being a carrier of two pathogenic variants. The variant reportedly classified as having a delayed (2B) transport from the endoplasmic reticulum to the cell surface, but is cited as VUS by reputable databases/clinical laboratories. Lastly, the codon Ala705 appears to be a hot spot, and another alteration, c.2113G>T (p.Ala705Ser) has been reported in association with Hypercholesterolaemia. Taken together the variant was classified as Pathogenic.
Invitae RCV000722114 SCV000627026 likely pathogenic Familial hypercholesterolemias 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 705 of the LDLR protein (p.Ala705Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with familial hypercholesterolemia (PMID: 11810272, 23375686, 18325082, 22095935, 21382890, 25412742). This variant is also known as p.A684P in the literature. ClinVar contains an entry for this variant (Variation ID: 36459). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
LDLR-LOVD, British Heart Foundation RCV000030132 SCV000295878 uncertain significance Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000030132 SCV000606601 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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