ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)

dbSNP: rs875989929
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237346 SCV000295624 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV002229692 SCV000544674 pathogenic Familial hypercholesterolemia 2022-11-20 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp558 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10978268, 23375686). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 252006). This variant is also known as p.Asp558Asn. This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 16542394). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 579 of the LDLR protein (p.Asp579Asn).
Illumina Laboratory Services, Illumina RCV000237346 SCV000914826 pathogenic Hypercholesterolemia, familial, 1 2018-10-19 criteria provided, single submitter clinical testing Across a selection of available literature, the LDLR c.1735G>A (p.Asp579Asn) variant, also known as p.Asp558Asn, has been reported in at least five studies and is found in at least seven probands with familial hypercholesterolemia in a heterozygous state (Hobbs et al. 1992; Ekstrom et al. 1995; Vuorio et al. 2001; Brusgaard et al. 2006). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database, with good sequence coverage of this region, and therefore it is presumed to be rare. Functional studies in cultured proband fibroblasts demonstrated that the p.Asp579Asn variant protein had 52% LDL binding, 42% internalization, and 46% degradation compared to control fibroblasts, suggesting that it had a binding-defective phenotype (Vuorio et al. 2001). Expression analysis in proband fibroblasts also found p.Asp579Asn to have 2% LDL receptor activity compared to controls (Hobbs et al. 1992). The Asp579 residue is highly conserved across species and x-ray crystallography demonstrated the importance of the Asp579 residue in hydrogen bonding necessary for structural formation (Ekstrom et al. 1995; Jeon et al. 2001). Based on the evidence, the p.Asp579Asn variant is classified as pathogenic for familial hypercholesterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000825595 SCV000966937 likely pathogenic Homozygous familial hypercholesterolemia 2018-05-04 criteria provided, single submitter clinical testing The p.Asp579Asn variant (also known as p.Asp558Asn, FH-Cinncinatti-4) in LDLR ha s been reported in 7 individuals with hypercholesterolemia (5 heterozygous, 1 do uble heterozygote with the p.Arg3527Gln variant in APOB, and one individual desc ribed by the authors as "compound heterozygote with an unidentified second varia nt"; Hobbs 1992, Ekstrom 1995, Jensen 1999, Brusgaard 2006, Pirillo 2017). This variant was absent from large population studies and is reported in ClinVar (Var iation ID: 252006). In vitro functional studies provide some evidence that the p .Asp5789Asn variant may result in transport defects and ER retention of the LDL receptor (Hobbs 1992). However, these types of assays may not accurately represe nt biological function. Computational prediction tools and conservation analysis suggest that the p.Asp579Asn variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. A different variant a t the same residue (p.Asp579Tyr) has been identified in >15 Italian individuals with hypercholesterolemia, suggesting change at this position may not be tolerat ed (Bertolini 2000). In summary, although additional studies are required to ful ly establish its clinical significance, the p.Asp579Asn variant is likely pathog enic. ACMG/AMP Criteria applied: PM2; PM5; PS4_Moderate; PP3; PS3_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284641 SCV001470530 pathogenic not provided 2019-10-21 criteria provided, single submitter clinical testing Not found in the gnomAD exomes dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
GeneDx RCV001284641 SCV002513146 uncertain significance not provided 2022-04-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that cultured fibroblasts from a patient with p.(D579N) and another unknown LDLR variant had <2% LDLR activity (Hobbs et al., 1992); however, the p.(D579N) variant was not studied in isolation and its functional effect in vivo is unknown; Also known as D558N, FH-Cincinnati-4; This variant is associated with the following publications: (PMID: 10532689, 11373616, 28965616, 7635461, 34037665, 31447099, 29874871, 31689621, 31401775, 11585102, 1301956, 16542394, 33955087)
Ambry Genetics RCV002411088 SCV002715718 pathogenic Cardiovascular phenotype 2022-02-16 criteria provided, single submitter clinical testing The p.D579N pathogenic mutation (also known as c.1735G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1735. The aspartic acid at codon 579 is replaced by asparagine, an amino acid with highly similar properties. This variant (also referred to as p.D558N) has been detected in the heterozygous, compound heterozygous, and homozygous states in individuals with definite or suspected heterozygous familial hypercholesterolemia (FH) and homozygous FH, as well as in individuals from FH cohorts and cohorts referred for FH genetic testing (Hobbs HH et al. Hum Mutat, 1992;1:445-66; Ekstr&ouml;m U et al. Hum Genet, 1995 Aug;96:147-50; Jensen HK et al. Clin Genet, 1996 Nov;50:388-92; Vuorio AF et al. Ann Med, 2001 Sep;33:410-21; Brusgaard K et al. Clin Genet, 2006 Mar;69:277-83; Di Taranto MD et al. Clin Genet, 2021 11;100:529-541; Benedek P et al. J Intern Med, 2021 08;290:404-415; Sturm AC et al. JAMA Cardiol, 2021 08;6:902-909). In addition, assays performed on cell lines from individuals with this variant demonstrated reduced protein function (Jensen HK et al. Clin Genet, 1996 Nov;50:388-92; Vuorio AF et al. Ann Med, 2001 Sep;33:410-21). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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