19-11105587-C-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM1PS3_ModeratePP3PP4PP1_StrongPS4
This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) variant, also known as ‘FH Afrikaner-1’ or ‘FH Maine’, is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PS3_Moderate, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 29 April 2022.The supporting evidence is as follows:PM2: PopMax MAF = 0.00002899 (0.003%) in Latino/Admixed American exomes (gnomAD v2.1.1).PP3: REVEL = 0.864. PM1: Variant meets PM2 and is missense located in exon 4.PS3_Moderate: Level 2 assay PMID 1301956 (Hobbs et al., 1992):Homozygous patient's fibroblasts studied with radiolabeled LDL results in 5-15% LDLR activity. Functional study is consistent with damaging effect.Level 2 assay PMID 2569482 (Leitersdorf et al., 1989):Partial cycle of LDLR studied in CHO Cells. WB after immunoprecipitation of radiolabelled LDLR variant show <50% of WT LDLR expression.PS4, PP4: Variant meets PM2 and is identified in 33 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=2 Robarts Research Institute; n=2 Color Health, Inc.; n=3 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=25 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA).PP1_Strong: Variant segregates with FH in at least 22 informatives meioses from at least 2 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia): 20 affected family members have the variant and 2 unaffected family members do not have the variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023747/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.681C>G | p.Asp227Glu | missense_variant | Exon 4 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 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 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:19
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 -
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NM_000527.5(LDLR):c.681C>G (p.Asp227Glu) variant, also known as ‘FH Afrikaner-1’ or ‘FH Maine’, is classified as Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS4, PP1_Strong, PS3_Moderate, PM1, PM2, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 29 April 2022. The supporting evidence is as follows: PM2: PopMax MAF = 0.00002899 (0.003%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3: REVEL = 0.864. PM1: Variant meets PM2 and is missense located in exon 4. PS3_Moderate: Level 2 assay PMID 1301956 (Hobbs et al., 1992): Homozygous patient's fibroblasts studied with radiolabeled LDL results in 5-15% LDLR activity. Functional study is consistent with damaging effect. Level 2 assay PMID 2569482 (Leitersdorf et al., 1989): Partial cycle of LDLR studied in CHO Cells. WB after immunoprecipitation of radiolabelled LDLR variant show <50% of WT LDLR expression. PS4, PP4: Variant meets PM2 and is identified in 33 index cases who fulfil SB criteria for FH (n=1 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) or DLCN criteria for FH (n=2 Robarts Research Institute; n=2 Color Health, Inc.; n=3 CGMC, UFGOD, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière; n=25 Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA). PP1_Strong: Variant segregates with FH in at least 22 informatives meioses from at least 2 families from different labs (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA, Australia): 20 affected family members have the variant and 2 unaffected family members do not have the variant. -
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subjects mutated among 2600 FH index cases screened = 6 , family members = 3 with co-segregation / FH-Afrikaner-1 / Software predictions: Damaging -
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. -
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. -
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Familial hypercholesterolemia Pathogenic:6
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. -
The c.681C>G (p.Asp227Glu) variant, also known as p.Asp206Glu, FH-Afrikaner-1, FH Maine, FH-1a and 4D in LDLR gene that encodes for low density lipoprotein receptor, has been identified in numerous individuals (>50) affected with familial hypercholesterolemia (FH) (PMID:8093663, 21310417, 27765764, 26892515, 23375686, 11810272, 17087781, 15199436, 9664576, 7718024, 1952806, 2569482, 8399083). This variant is a founder allele in the Afrikaner population and has been shown to segregate with disease in many families (PMID: 2352257, 11491306, 8399083). This variant lies in the well-established LDL binding domain (amino acids 105-232) critical for protein function (PMID: 2600087). In-silico computational prediction tools suggest that the p.Asp227Glu variant may have deleterious effect on the protein function (REVEL score: 0.864). This variant is found to be rare (2/248142; 0.00000806) in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 3690). Therefore, the c.681C>G (p.Asp227Glu) variant in LDLR gene is classified as pathogenic. -
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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). 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 Asp206Glu and FH Afrikaner-1. ClinVar contains an entry for this variant (Variation ID: 3690). 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 affects LDLR function (PMID: 2569482). For these reasons, this variant has been classified as Pathogenic. -
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. -
not provided Pathogenic:3
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) -
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PS1, PS3, PS4, PM1, PM2, PM3, PM5, PP3 -
Cardiovascular phenotype Pathogenic:1
The p.D227E pathogenic mutation (also known as c.681C>G), located in coding exon 4 of the LDLR gene, results from a C to G substitution at nucleotide position 681. The aspartic acid at codon 227 is replaced by glutamic acid, an amino acid with highly similar properties. This founder mutation (also referred to as p.D206I accounts for the majority of familial hypercholesterolemia (FH) in the Afrikaner population (Leitersdorf et al. J Clin Invest.1989;84(3):954-61; King et al. N Z Med J. 2010;123(1319):79-82). This alteration has been reported in affected individuals of multiple ethnicities in both the heterozygous and homozygous states (e.g., Gudnason et al. Arterioscler. Thromb. 1993;13(1):56-63; Leren et al. Semin Vasc Med. 2004;4(1):75-85; Bertolini et al Atherosclerosis 2013;227(2):342-348; Sharifi et al. Metab. Clin. Exp. 2016;65(3):48-53). In an assay testing LDLR function, this variant showed a functionally abnormal result (Fourie A et al. Biochem J. 1988;255(2):411-5). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at