chr19-11105587-C-G
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000527.5(LDLR):c.681C>G(p.Asp227Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,605,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D227G) has been classified as Pathogenic.
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.681C>G | p.Asp227Glu | missense_variant | 4/18 | ENST00000558518.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.681C>G | p.Asp227Glu | missense_variant | 4/18 | 1 | NM_000527.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152024Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000806 AC: 2AN: 248142Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135108
GnomAD4 exome AF: 0.0000213 AC: 31AN: 1453262Hom.: 0 Cov.: 34 AF XY: 0.0000222 AC XY: 16AN XY: 721214
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74392
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:18
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | research | Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia | Jun 05, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Robarts Research Institute, Western University | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 21, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid (exon 4). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Ldl_recept_a domain and is a calcium binding site; NCBI). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, criteria provided, single submitter | clinical testing | U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Mar 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Dec 16, 2016 | subjects mutated among 2600 FH index cases screened = 6 , family members = 3 with co-segregation / FH-Afrikaner-1 / Software predictions: Damaging - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 29, 2022 | The p.Asp227Glu variant in LDLR has been reported in >20 heterozygous individuals with familial hypercholesterolemia and segregated in at least 10 affected family members (Gudnason 1993 PMID: 8093663, Callis 1998 PMID: 9664576, Chan 2019 PMID: 30592178, Fouchier 2001 PMID: 11810272, Sharifi 2016 PMID: 26892515, Trinder 2019 PMID: 31345425, van der Graaf 2011 PMID: 21382890). It has been reported as the FH Afrikaner 1 allele, a founder variant in the white Afrikaner-speaking population of South Africa, and is thought to account for 65 - 75% of familial hypercholesterolemia in this population (Leitersdorf 1989 PMID: 2569482, Kotze 1990 PMID: 2352257 , Kotze 1994 PMID: 8399083). It has been reported in ClinVar (Variation ID 3690) and in several patients with homozygous FH (Leitersdorf 1989 PMID: 2569482, Bertolini 2013 PMID: 23375686, Pirillo 2017 PMID: 28965616, Truong 2018 PMID: 30270076, Luirink 2019 PMID: 31048103). The c.681C>G, p.(Asp227Glu) variant has also been reported with legacy nomenclature as D206E. Additionally, in vitro functional studies provide some evidence that the p.Asp227Glu variant may impair receptor activity (Fourie 1988 PMID: 3202825). This variant has been identified in 1/34492 of Latino/Admixed American and in 1/112078 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. In summary, this variant meets criteria to be classified as pathogenic for FH. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting. - |
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Pathogenic, criteria provided, single submitter | curation;literature only | Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Mar 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 10, 2024 | This variant (also known as p.Asp206Glu in the mature protein and as FH-Afrikaner-1, FH Maine, FH-1a, and 4D) is a missense variant located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Experimental functional studies have indicated that the variant may impair LDLR activity (PMID: 6324732, 3202825, 2569482, 1301956, 1463746). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2569482, 2352257, 11491306) and has been reported in numerous unrelated individuals affected with familial hypercholesterolemia from multiple ethnicities (PMID: 2569482, 2352257 1952806, 8093663, 7718024, 9664576, 11491306, 15199436, 17087781, 11810272, 21310417, 23375686, 26892515, 27765764, 33955087, 33994402, 34297352). This variant has been identified in 2/244544 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Jun 25, 2008 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 27, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 21, 2022 | - - |
Familial hypercholesterolemia Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 24, 2023 | Variant summary: LDLR c.681C>G (p.Asp227Glu) results in a conservative amino acid change located in the fifth class A repeat domain (IPR002172) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248142 control chromosomes (gnomAD). c.681C>G has been reported in the literature in the heterozygous, homozygous, or compound heterozygous state in numerous individuals affected with Familial Hypercholesterolemia (e.g. Kotze_1990, Gudnason_1994, Bertolini_2013, Sharifi_2016, Thedrez_2018). The variant has also been described as a founder variant within the Afrikaner population and it has been estimated that approximately 65% of affected South African Afrikaners carry this variant (Kotze_1990). These data indicate that the variant is very likely to be associated with disease. Publications reporting experimental evidence evaluating an impact on protein function found slower processing and decreased cell surface expression for the variant protein (e.g. Leitersdorf_1989, Thedrez_2018). The following publications have been ascertained in the context of this evaluation (PMID: 23375686, 7947594, 2352257, 2569482, 26892515, 29284604). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=16)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2023 | This variant (also known as p.Asp206Glu in the mature protein and as FH-Afrikaner-1, FH Maine, FH-1a, and 4D) is a missense variant located in the fifth LDLR type A repeat in the ligand binding domain of the LDLR protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have indicated that the variant may impair LDLR activity (PMID: 6324732, 3202825, 2569482, 1301956, 1463746). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2569482, 2352257, 11491306) and has been reported in numerous unrelated individuals affected with familial hypercholesterolemia from multiple ethnicities (PMID: 2569482, 2352257 1952806, 8093663, 7718024, 9664576, 11491306, 15199436, 17087781, 11810272, 21310417, 23375686, 26892515, 27765764, 33955087, 33994402, 34037665, 34297352). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 36229885). This variant has been identified in 2/248142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 227 of the LDLR protein (p.Asp227Glu). This variant is present in population databases (rs121908028, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2352257, 2569482, 17539906, 19467224, 21310417, 21382890, 22883975, 23375686, 23669246, 27680772). It is commonly reported in individuals of Afrikaner ancestry (PMID: 2352257, 2569482). This variant is also known as Asp206Glu and FH Afrikaner-1. ClinVar contains an entry for this variant (Variation ID: 3690). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand | Jul 01, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 02, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jan 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 21, 2021 | PS1, PS3, PS4, PM1, PM2, PM3, PM5, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2022 | Disrupts a negatively charged triplet, Ser-Asp-Glu, located at the carboxyl-terminal end of the LDL- receptor class A5 repeat domain that is critical for ligand binding (Schneider et al., 2003); Functional studies demonstrate a damaging effect: creation of two LDLR isoforms, both with a slower maturation process, and one with inability to bind to the lipoprotein ligand resulting in a reduced rate of lipoprotein degradation (Leitersdorf et al., 1989; Fourie et al., 1992); Common founder variant in the Afrikaner population (Kotze et al., 1993); 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; This variant is associated with the following publications: (PMID: 3202825, 2352257, 23375686, 2569482, 11810272, 26892515, 8093663, 9664576, 17087781, 2565980, 1463746, 30270076, 31048103, 29284604, 31447099, 32977124, 32041611, 32922439, 33740630, 34037665, 33087929, 28965616, 30592178, 27680772, 12827279, 3430554, 8399083) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2024 | The c.681C>G (p.D227E) alteration is located in exon 4 (coding exon 4) of the LDLR gene. This alteration results from a C to G substitution at nucleotide position 681, causing the aspartic acid (D) at amino acid position 227 to be replaced by a glutamic acid (E). Based on data from gnomAD, the G allele has an overall frequency of 0.001% (2/248142) total alleles studied. The highest observed frequency was 0.003% (1/34492) of Latino alleles. This founder mutation, previously reported as p.D206E, accounts for the majority of familial hypercholesterolemia (FH) in the Afrikaner population (Leitersdorf, 1989; King, 2010). This alteration has been reported in affected individuals of multiple ethnicities in both the heterozygous and homozygous states (Gudnason, 1993; Leren, 2004; Bertolini, 2013; Sharifi, 2016). This amino acid position is highly conserved in available vertebrate species. In cultured fibroblasts, LDL receptors carrying this mutation were observed to synthesize mature protein; however, conversion to mature receptor protein was severely impaired and ligand binding activity was reduced to 20% of wildtype (Fourie, 1988). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at