ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.910G>A (p.Asp304Asn) (rs121908030)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003880 SCV000295045 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003880 SCV000540769 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
Invitae RCV000791377 SCV000544684 pathogenic Familial hypercholesterolemia 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 304 of the LDLR protein (p.Asp304Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs121908030, ExAC <0.01%). This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 9664576, 11810272, 12436241, 2088165, 21418584, 22698793). This variant is also known as Denver-2 and D283N. ClinVar contains an entry for this variant (Variation ID: 3692). A different missense substitution at this codon (p.Asp304Glu) has been determined to be pathogenic (PMID: 1301956, 17094996). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. Experimental studies have shown that this missense change reduces the LDLR receptor activity (PMID: 1301956). For these reasons, this variant has been classified as Pathogenic.
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003880 SCV000583757 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003880 SCV000599350 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter curation
Ambry Genetics RCV000622705 SCV000741389 likely pathogenic Inborn genetic diseases 2017-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000003880 SCV000840002 pathogenic Familial hypercholesterolemia 1 2018-04-10 criteria provided, single submitter clinical testing This c.910G>A (p.Asp304Asn) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9664576, 11810272, 12436241, 21418584, 21310417) and is extremely rare in the general population. Functional studies have shown that the mutant LDLR protein retains only 5-15% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). This c.910G>A (p.Asp304Asn) variant in the LDLR gene is classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826215 SCV000967783 pathogenic Familial hypercholesterolemia - homozygous 2018-04-06 criteria provided, single submitter clinical testing The p.Asp304Asn variant in LDLR (also described as p.Asp283Asn in the literature ) has been reported in at least 14 individuals (in at least 1 in the homozygous state and at least 13 in the heterozygous state) with familial hypercholesterol emia (FH; Hobbs 1990, Callis 1998, Fouchier 2001, Ansellem 2002, Al-Khateeb 2011 , Tichy 2012, Do 2015). In vitro functional studies provide some evidence that t he p.Asp304Asn variant may impact protein function (Hobbs 1990). This variant ha s also been reported by other clinical laboratories in ClinVar (Variation ID: 36 92) and has been identified in 3/24012 African chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908030). Thi s frequency is consistent with the frequency of FH in the general population. Co mputational prediction tools and conservation analysis suggest that the p.Asp304 Asn variant may impact the protein. In addition, four other variants at this pos ition have been reported in individuals with FH (HGMD database, Stenson 2017), w ith at least one classified as likely pathogenic or pathogenic, suggesting that changes at this position are not tolerated. In summary, this variant meets crit eria to be classified as pathogenic for FH in an autosomal dominant manner based upon presence in multiple affected individuals, low frequency in the general po pulation, the presence of a different pathogenic variant at the same codon, and functional and computational evidence. ACMG/AMP Criteria applied (Richards 2015) : PS4; PM2; PM5; PP3; PS3_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985772 SCV001134272 pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
OMIM RCV000003880 SCV000024045 pathogenic Familial hypercholesterolemia 1 1988-11-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148569 SCV000190282 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003880 SCV000606264 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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