Submissions for variant NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)

gnomAD frequency: 0.00009  dbSNP: rs151207122

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238462	SCV001960917	uncertain significance	Hypercholesterolemia, familial, 1	2021-06-08	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.907C>T (p.Arg303Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.815. It is above 0.75, so PP3 is Met.
LDLR-LOVD, British Heart Foundation	RCV000238462	SCV000295044	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
GeneDx	RCV000657894	SCV000779658	uncertain significance	not provided	2022-06-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R282W); This variant is associated with the following publications: (PMID: 25637381, 25487149, 31106297, 32977124, 32719484, 33955087, 24507775, 28965616, 9544746, 35741760, 34040191)
Invitae	RCV000791388	SCV000825564	pathogenic	Familial hypercholesterolemia	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 303 of the LDLR protein (p.Arg303Trp). This variant is present in population databases (rs151207122, gnomAD 0.04%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9544746, 24507775, 28965616, 34040191; Invitae). This variant is also known as p.Arg282Trp and R282W. ClinVar contains an entry for this variant (Variation ID: 161281). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781501	SCV000919581	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.907C>T (p.Arg303Trp) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251326 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4.8e-05 vs 0.0013), allowing no conclusion about variant significance. c.907C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Arca_1997, Pirillo_2017, Ajufo_2021, Rutkowska_2022, Okada_2022, Young__2022). These data indicate that the variant may be associated with disease. The Arg303 codon and adjacent codons have been implicated in Familial Hypercholesterolemia (e.g., p.303Q p.C302R, p.C302W, p.D304N, p.D304E), suggesting the codon and region may be a mutational hotspot and critical for protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34040191, 25637381, 9544746, 32977124, 34906454, 25487149, 24507775, 36184534, 28965616, 35741760, 31106297, 36229376, 33079599, 31345425, 36507290). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=8, including one expert panel, ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000791388	SCV001346462	uncertain significance	Familial hypercholesterolemia	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant (also known as p.Arg282Trp in the mature protein) replaces arginine with tryptophan at codon 303 of the LDLR protein. Computational prediction suggests that this variant may have a 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 individuals affected with familial hypercholesterolemia (PMID: 9544746, 28965616, 31345425, 34040191). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia (PMID: 32977124, 36507290). This variant has been identified in 13/282676 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.
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	RCV000238462	SCV001432670	uncertain significance	Hypercholesterolemia, familial, 1	2019-05-10	criteria provided, single submitter	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000657894	SCV001715243	uncertain significance	not provided	2022-08-11	criteria provided, single submitter	clinical testing	PP3
Ambry Genetics	RCV002444607	SCV002683064	uncertain significance	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The p.R303W variant (also known as c.907C>T), located in coding exon 6 of the LDLR gene, results from a C to T substitution at nucleotide position 907. The arginine at codon 303 is replaced by tryptophan, an amino acid with dissimilar properties. This variant (also referred to as R282W) has been detected in cohorts with hypercholesterolemia; however, in several cases, clinical details were limited, and, in one case, it co-occurred with another variant in LDLR (Arca M. Atherosclerosis. 1998 Jan;136(1):187-94; Pirillo A et al. Atheroscler Suppl, 2017 Oct;29:17-24; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Sun YV et al. Circ Genom Precis Med, 2018 12;11). This variant has also been detected in an early onset myocardial infarction (MI) cohort and MI-free controls, as well as in a low LDL-C and healthy exome cohorts (Do R et al. Nature, 2015 Feb;518:102-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). This alteration impacts a residue in the conserved cluster of acidic amino acids at the C-terminal end of LDLR class A repeat 7 (Jeon H and Blacklow C. Annu. Rev. Biochem. 2005;74:535-62). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000238462	SCV002782736	uncertain significance	Hypercholesterolemia, familial, 1	2021-11-17	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV002051674	SCV000190302	uncertain significance	Hypercholesterolemia	2014-06-01	no assertion criteria provided	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238462	SCV000606263	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000791388	SCV002086393	uncertain significance	Familial hypercholesterolemia	2020-09-24	no assertion criteria provided	clinical testing