ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala)

gnomAD frequency: 0.00008  dbSNP: rs138315511
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000030124 SCV004022472 uncertain significance Hypercholesterolemia, familial, 1 2023-04-28 reviewed by expert panel curation The NM_000527.5(LDLR):c.1085A>C (p.Asp362Ala) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4 and PS4_Moderate) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.0001782 (0.01782%) in European (non-Finnish) exomes+genomes (gnomAD v2.1.1). PS4_Moderate - Variant meets PM2 and is identified in 8 unrelated index cases (5 cases with Simon-Broome criteria of definite/possible FH published in PMID: 16542394, Denmark; at least 1 case with DLCN>=6 published in PMID: 11810272, Netherlands; 1 case with DLCN criteria >=6 from Robarts Research Institute, Canada; 1 case with Simon-Broome criteria of possible FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), Czechia. PP4 - Variant meets PM2 and is identified in at least one case who fufills clinical criteria for FH (see PS4 for details), after alternative causes of high cholesterol were excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030124 SCV000052779 likely pathogenic Hypercholesterolemia, familial, 1 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Cardiovascular Biomarker Research Laboratory, Mayo Clinic RCV000030124 SCV000266320 uncertain significance Hypercholesterolemia, familial, 1 2016-02-19 criteria provided, single submitter research MAF =<0.3%, likely pathogenic based on the integrative in-silico score, previously reported as P/LP in the literature
LDLR-LOVD, British Heart Foundation RCV000030124 SCV000295209 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Robarts Research Institute, Western University RCV000030124 SCV000484750 likely pathogenic Hypercholesterolemia, familial, 1 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000775055 SCV000909155 uncertain significance Familial hypercholesterolemia 2024-01-08 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with alanine at codon 362 of the LDLR protein. This variant is also known as p.Asp341Ala in the mature protein. This variant alters a conserved aspartic acid residue in the EGF-like repeat B of the LDLR protein (a.a. 355-393), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 27765764, 33740630; Color internal data) and in one individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 23/282712 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000030124 SCV001422628 uncertain significance Hypercholesterolemia, familial, 1 2020-01-22 criteria provided, single submitter curation The p.Asp362Ala variant in LDLR has been reported in 8 individuals (including 5 Danish and 1 Dutch individuals) with Familial Hypercholesterolemia (PMID: 27765764, 11810272, 16542394, 28145427), and has been identified in 0.01782% (23/129086) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138315511). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a benign variant, likely benign variant, VUS, and likely pathogenic variant (Variation ID: 36452). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PP3 (Richards 2015).
Ambry Genetics RCV002426524 SCV002729423 uncertain significance Cardiovascular phenotype 2023-08-07 criteria provided, single submitter clinical testing The p.D362A variant (also known as c.1085A>C and legacy p.D341A), located in coding exon 8 of the LDLR gene, results from an A to C substitution at nucleotide position 1085. The aspartic acid at codon 362 is replaced by alanine, an amino acid with dissimilar properties. This variant has been reported in individuals with familial hypercholesterolemia; however, some individuals had additional LDLR variants also detected, and clinical details were limited for some cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15, Damgaard D et al. Atherosclerosis, 2005 May;180:155-60; Brusgaard K et al. Clin. Genet., 2006 Mar;69:277-83; Wang J et al. Arterioscler. Thromb. Vasc. Biol., 2016 12;36:2439-2445; Rieck L et al. Clin Genet, 2020 11;98:457-467; Leren TP et al. Atherosclerosis, 2021 04;322:61-66). This variant was also reported in an early onset myocardial infarction cohort in cases and control subjects (Do R et al. Nature, 2015 Feb;518:102-6). Furthermore, it has been reported in healthy population and exome cohorts where cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239; Shickh S et al. J Med Genet, 2021 04;58:275-283). 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 limited at this time, the clinical significance of this alteration remains unclear.
Department of Medical Genomics, Royal Prince Alfred Hospital RCV000775055 SCV002756460 likely pathogenic Familial hypercholesterolemia 2022-11-28 criteria provided, single submitter clinical testing The variant is present in multiple individuals with clinically diagnosed FH tested by this laboratory (50yo Male, DLCNS=6) and described in the literature, and is found at an extremely low frequency in control populations (gnomAD frequency 0.01782%).
Invitae RCV000775055 SCV003261897 uncertain significance Familial hypercholesterolemia 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 362 of the LDLR protein (p.Asp362Ala). This variant is present in population databases (rs138315511, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of LDLR-related conditions (PMID: 11810272, 15823288, 16542394, 25487149, 27765764, 33303402). ClinVar contains an entry for this variant (Variation ID: 36452). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health RCV000030124 SCV004820265 uncertain significance Hypercholesterolemia, familial, 1 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with alanine at codon 362 of the LDLR protein. This variant is also known as p.Asp341Ala in the mature protein. This variant alters a conserved aspartic acid residue in the EGF-like repeat B of the LDLR protein (a.a. 355-393), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 27765764, 33740630; Color internal data) and in one individual affected with isolated hypercholesterolemia (PMID: 33303402). This variant has been identified in 23/282712 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.
CSER _CC_NCGL, University of Washington RCV002051646 SCV000190276 likely benign Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000030124 SCV000606323 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research

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