ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1553A>G (p.Lys518Arg)

dbSNP: rs879254938
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238265 SCV002817130 uncertain significance Hypercholesterolemia, familial, 1 2022-08-26 reviewed by expert panel curation The NM_000527.5 (LDLR):c.1553A>G (p. Lys518Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS4_Supporting, BP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in ˃1 index case who fulfil criteria for FH diagnosis from 2 labs after alternative causes of high cholesterol were excluded. PS4_Supporting: Variant meets PM2 and is identified in 2 unrelated index cases who fulfil FH diagnosis criteria. One index case met MedPed definite FH criteria from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); one index case fulfil Simon Broome criteria for FH, reported by Usifo et al, 2012, British Heart Foundation Laboratories, Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK (PMID22881376). BP4: REVEL = 0.371, it is below 0.5, splicing evaluation required. Variant is exonic and is not on limit creating de novo acceptor site. It is located at least 50bp downstream from canonical acceptor site but does not create GT. Variant is not predicted to alter splicing. PP3 not met: REVEL = 0.371, it is not above 0.75. Alternative splicing is not predicted. PS3 not met: Functional data on splicing is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.1552A>G (p.Lys518Glu) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
LDLR-LOVD, British Heart Foundation RCV000238265 SCV000295494 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
CeGaT Center for Human Genetics Tuebingen RCV000996755 SCV001151663 uncertain significance not provided 2019-06-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001183444 SCV001349164 uncertain significance Familial hypercholesterolemia 2023-10-12 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 518 of the LDLR protein. This variant is also known as p.Lys497Arg in the mature protein. This variant alters a conserved lysine residue in the LDLR type B repeat 3 of the EGF precursor homology domain in the LDLR protein (a.a. 486 - 528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 22881376; Color internal data). This variant has been identified in 1/251378 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.
All of Us Research Program, National Institutes of Health RCV000238265 SCV004822475 uncertain significance Hypercholesterolemia, familial, 1 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 518 of the LDLR protein. This variant is also known as p.Lys497Arg in the mature protein. This variant alters a conserved lysine residue in the LDLR type B repeat 3 of the EGF precursor homology domain in the LDLR protein (a.a. 486 - 528), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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: 22881376; Color internal data). This variant has been identified in 1/251378 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.

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