ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.139G>A (p.Asp47Asn)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238312 SCV001960940 uncertain significance Hypercholesterolemia, familial, 1 2021-06-07 reviewed by expert panel curation The NM_000527.5(LDLR):c.139G>A (p.Asp47Asn) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (BS3, PM2 and PP4) 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: BS3 - Level 1 assays: PMID 30413722: Heterologous cells (CHO-ldlA7), FACS and western blot assays - result - Normal (>90%) expression, binding and uptake ---- whole cycle is above 90% of wild-type activity, so BS3 is Met. PM2 - PopMax MAF = 0.0001307 (0.013%) in South Asian exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in at least 1 FH case from Laboratory of Genetics and Molecular Cardiology who fulfill Simon-Broome criteria.
LDLR-LOVD, British Heart Foundation RCV000238312 SCV000294483 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238312 SCV000503104 uncertain significance Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / FH-Hyogo / Software predictions: Damaging
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000238312 SCV000588486 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001377111 SCV001574347 pathogenic Familial hypercholesterolemia 2023-10-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 47 of the LDLR protein (p.Asp47Asn). This variant is present in population databases (rs778284147, gnomAD 0.01%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11313767, 11857755, 18718593, 29399563, 33547002; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as D26N. ClinVar contains an entry for this variant (Variation ID: 251034). 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. Experimental studies have shown that this missense change does not substantially affect LDLR function (PMID: 30413722). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002392738 SCV002701734 uncertain significance Cardiovascular phenotype 2022-01-18 criteria provided, single submitter clinical testing The c.139G>A (p.D47N) alteration is located in coding exon 2 of the LDLR gene. This alteration results from a G to A substitution at nucleotide position 139, causing the aspartic acid (D) at amino acid position 47 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (4/251226) total alleles studied. The highest observed frequency was 0.01% (4/30614) of South Asian alleles. This alteration has been reported in several familial hypercholesterolemia (FH) cohorts (Varret, 1998; Heath, 2001; Bunn, 2002; Miyake, 2009; Kim, 2018). It has also been detected in the heterozygous state in an individual diagnosed with homozygous FH, though no second variant was identified (Huang, 2015). This amino acid position is highly conserved in available vertebrate species. Functional studies suggest that this alteration does not impact protein function (Benito-Vicente, 2018). This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000238312 SCV002779607 uncertain significance Hypercholesterolemia, familial, 1 2022-04-13 criteria provided, single submitter clinical testing
GeneDx RCV003328575 SCV004035579 uncertain significance not provided 2023-08-31 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Functional studies with transfected CHO-IDlA7 cells showed similar binding and update as the wild-type (Benito-Vicente et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(D26N) and FH Hyogo; This variant is associated with the following publications: (PMID: 18718593, 33547002, 32331935, 11313767, 9399845, 29399563, 11857755, 25911080, 30413722, 31491741)
Color Diagnostics, LLC DBA Color Health RCV001377111 SCV004358467 likely pathogenic Familial hypercholesterolemia 2023-06-13 criteria provided, single submitter clinical testing This missense variant (also known as p.Asp26Asn in the mature protein, and as FH Hyogo) replaces aspartic acid with asparagine in the first LDLR-A repeat in codon 47 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). A functional study reported that this variant does not cause a defect in LDLR expression and function (PMID: 30413722). This LDLR variant has been reported in over 15 heterozygous individuals affected with familial hypercholesterolemia (PMID 11313767, 11857755, 18718593, 29399563, 32331935, 33547002, 33533259, 35319679, 35929461; communication with an external laboratory; ClinVar variation ID: 251034). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 35319679). It has been shown that this variant segregates with disease in 6 affected individuals from two unrelated families (communication with an external laboratory; ClinVar variation ID: 251034); some individuals carrying this variant did not show elevated cholesterol levels, reflecting incomplete penetrance. This variant has been identified in 4/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health RCV000238312 SCV004820119 likely pathogenic Hypercholesterolemia, familial, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant (also known as p.Asp26Asn in the mature protein, and as FH Hyogo) replaces aspartic acid with asparagine in the first LDLR-A repeat in codon 47 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). A functional study reported that this variant does not cause a defect in LDLR expression and function (PMID: 30413722). This LDLR variant has been reported in over 15 heterozygous individuals affected with familial hypercholesterolemia (PMID 11313767, 11857755, 18718593, 29399563, 32331935, 33547002, 33533259, 35319679, 35929461; communication with an external laboratory; ClinVar variation ID: 251034). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 35319679). It has been shown that this variant segregates with disease in 6 affected individuals from two unrelated families (communication with an external laboratory; ClinVar variation ID: 251034); some individuals carrying this variant did not show elevated cholesterol levels, reflecting incomplete penetrance. This variant has been identified in 4/251226 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238312 SCV000606024 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Iberoamerican FH Network RCV000238312 SCV000748172 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 no assertion criteria provided research

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