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

dbSNP: rs879254938

Total submissions: 6

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	2024-03-05	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001183444	SCV005800779	uncertain significance	Familial hypercholesterolemia	2024-06-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 518 of the LDLR protein (p.Lys518Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 251895). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.