NM_000527.5:c.58G>A
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. BS3BS4PP1_ModerateBS2
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database.BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met.BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy.Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023728/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LDLR | NM_000527.5 | c.58G>A | p.Gly20Arg | missense_variant | Exon 1 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000513 AC: 78AN: 152140Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000743 AC: 182AN: 245116Hom.: 0 AF XY: 0.000838 AC XY: 112AN XY: 133624
GnomAD4 exome AF: 0.000423 AC: 617AN: 1459798Hom.: 1 Cov.: 31 AF XY: 0.000442 AC XY: 321AN XY: 726128
GnomAD4 genome 0.000512 AC: 78AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41AN XY: 74460
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:5Benign:4
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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A functional analysis was previously published (Pavloušková et al, 2016). This variant has no effect on LDLR protein function. -
0/190 non-FH alleles; 0/150 normolipidemic chromosomes -
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The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign. -
MAF =<0.3%. "Little/No effect" on the LDL receptor activity based on experimental validation. -
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Familial hypercholesterolemia Benign:4
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not provided Benign:3Other:1
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LDLR: BS3:Supporting, BS1, BS2 -
not specified Benign:3
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Variant summary: LDLR c.58G>A (p.Gly20Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00077 in 255636 control chromosomes, predominantly at a frequency of 0.0024 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is approximately 2-fold the estimated maximum allele frequency expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.58G>A has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia, however without evidence for co-segrgation with disease. In a family with Familial Hypercholesterolemia (FH), 1 transmission of the variant allele and 1 transmission of the reference allele to affected individuals was reported (Medeiros_2014). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants in LDLR have also been reported in FH patients in the literature (examples- Tejedor_2011, Komarova_2013, Klancar_2015), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, showing no damaging effects by this variant (examples- Thormaehlen_2015, Pavlouskova_2016). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=5; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Hypercholesterolemia Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
LDLR-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at