ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.949G>A (p.Glu317Lys) (rs746834464)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237913 SCV000295106 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237913 SCV000583768 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV001176042 SCV001339859 uncertain significance Familial hypercholesterolemia 2020-07-14 criteria provided, single submitter clinical testing This missense variant (also known as p.Glu296Lys in the mature protein) replaces glutamic acid with lysine at codon 317 of the LDLR 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 two individuals affected with familial hypercholesterolemia (PMID: 20145306). This variant has been identified in 15/282452 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237913 SCV000606284 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000237913 SCV001422634 uncertain significance Familial hypercholesterolemia 1 2020-01-23 no assertion criteria provided curation The p.Glu317Lys variant in LDLR has been reported in at least 2 individuals (including 1 Polish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 20145306) and 2 individuals with probable Familial Hypercholesterolemia (Variation ID: 251567), and has been identified in 0.02940% (9/30610) of South Asian chromosomes and 0.004010% (1/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746834464). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. 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 variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 251567). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region (a ligand binding repeat) as p.Glu317Lys have been reported in association with disease in ClinVar and the literature, suggesting that this variant is in a mutational hot spot with functional importance and supports pathogenicity (PMID: 20145306; Variation ID: 251566, 183103, 251570, 251572, 251571). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1, PP3, PS4_Supporting (Richards 2015).
Clinical Genetics,Academic Medical Center RCV001699171 SCV001918745 likely pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001699171 SCV001957243 pathogenic not provided no assertion criteria provided clinical testing

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