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

Total submissions: 13

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377111	SCV001574347	pathogenic	Familial hypercholesterolemia	2024-12-11	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; internal data). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. This variant is also known as D26N. ClinVar contains an entry for this variant (Variation ID: 251034). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. 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	2024-07-10	criteria provided, single submitter	clinical testing	The p.D47N variant (also known as c.139G>A), located in coding exon 2 of the LDLR gene, results from a G to A substitution at nucleotide position 139. The aspartic acid at codon 47 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several familial hypercholesterolemia (FH) cohorts (Varret M et al. Nucleic Acids Res., 1998 Jan;26:248-52; Heath KE et al. Eur. J. Hum. Genet., 2001 Apr;9:244-52; Bunn CF et al. Hum. Mutat., 2002 Mar;19:311; Kim HN et al. Chonnam Med J, 2018 Jan;54:31-35). It has also been detected in the heterozygous state in an individual diagnosed with homozygous FH, though no second variant was identified (Huang CH et al. J Clin Lipidol Dec;9:234-40). However, functional studies suggest that this alteration does not impact protein function (Benito-Vicente A et al. Sci Rep, 2018 11;8:16614). 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 (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, 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	2024-09-13	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003328575	SCV005625814	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	The LDLR c.139G>A (p.Asp47Asn) variant also known as FH Hyogo) has been reported in the published literature in individuals with Familial hypercholesterolemia (PMIDs: 32331935 (2020), 31491741 (2019), 29399563 (2018), 25911080 (2015), 18718593 (2009), 11857755 (2002), and 11313767 (2001)). It was also reported in a family with suspected Familial hypercholesterolemia (PMID: 33547002 (2021)) and in an individual with Familial hypercholesterolemia as well as in a reportedly healthy individual (PMID: 27050191 (2016)). A functional study found that this variant was not damaging to protein function (PMID: 30413722 (2018)). The frequency of this variant in the general population, 0.00013 (4/30614 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
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