ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.967G>A (p.Gly323Ser) (rs373869746)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238216 SCV000295115 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238216 SCV000503269 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging
Color Health, Inc RCV001181337 SCV001346463 uncertain significance Familial hypercholesterolemia 2020-10-08 criteria provided, single submitter clinical testing This missense variant (also known as p.Gly302Ser in the mature protein) replaces glycine with serine at codon 323 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 an individual affected with familial hypercholesterolemia (PMID: 15823288). This variant has been identified in 6/282324 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.
CSER _CC_NCGL, University of Washington RCV000148589 SCV000190303 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Broad Institute Rare Disease Group, Broad Institute RCV000238216 SCV001422785 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Gly323Ser variant in LDLR has been reported in at least 2 individuals (including 1 Danish individual) with Familial Hypercholesterolemia (PMID: 15823288, 25637381), and has been identified in 0.02008% (5/24906) of African chromosomes and 0.003267% (1/30606) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs373869746). 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 as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 161282). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Gly323Ser variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting (Richards 2015).

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