rs370471092
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS4_SupportingPP4PM2
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.00002 (0.002%) in European (Non-Finnish) in genomes+exomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 cases (1 with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 with DLCN score >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case in PMID 33994402 (Huang et al., 2022), Taiwan, and 1 case in PMID 34998859 (Pillai et al., 2022), India, with country-specific FH criteria), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023410/MONDO:0007750/013
Frequency
Consequence
NM_000527.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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LDLR | NM_000527.5 | c.1057G>A | p.Glu353Lys | missense_variant | Exon 7 of 18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000599 AC: 15AN: 250574Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135570
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1460818Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 726754
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74340
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:4
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This missense variant (also known as p.Glu332Lys in the mature protein) replaces glutamic acid with lysine at codon 353 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408; Huang et al, 2021, doi.org/10.5551/jat.62773), as well as in an individual affected with premature myocardial infarction (PMID: 30971288). This variant has also been identified in 16/281978 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. -
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Familial hypercholesterolemia Pathogenic:1Uncertain:4
Variant summary: LDLR c.1057G>A (p.Glu353Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250574 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (6e-05 vs 0.0013), allowing no conclusion about variant significance. c.1057G>A has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypercholesterolemia (example, Kusters_2013, Pillai_2022, Reijman_2023) however it has also been observed in at least 1 person with a history of myocardial infarction but no significant elevation in LDL-C (example, Thormaehlen_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity and was considered an "unclear" result by the authors (example, Thormaehlen_2015). The following publications have been ascertained in the context of this evaluation (PMID: 23833242, 34998859, 36752612, 25647241). ClinVar contains an entry for this variant (Variation ID: 161275). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 353 of the LDLR protein (p.Glu353Lys). This variant is present in population databases (rs370471092, gnomAD 0.03%). This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction (PMID: 11810272, 15823288, 20506408, 25647241, 27828139, 27878139, 30971288). This variant is also known as p.Glu332Lys. ClinVar contains an entry for this variant (Variation ID: 161275). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 25647241). 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. -
This missense change has been observed in individual(s) with familial hypercholesterolemia and myocardial infarction .This variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. -
This missense variant replaces glutamic acid with lysine at codon 353 of the LDLR protein. This variant is also known as p.Glu332Lys in the mature protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. A functional study using transfected HeLa cells has shown inconclusive results regarding this variant's impact on LDLR expression (PMID: 25647241). This variant has been reported in four individuals affected with familial hypercholesterolemia (PMID: 11810272, 15823288, 20506408, 33994402, 34998859), as well as in one individual affected with premature myocardial infarction (PMID: 30971288). This variant has been identified in 16/281978 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. -
not provided Uncertain:1Other:1
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The LDLR c.1057G>A (p.Glu353Lys) variant (also known as E332K) has been reported in the published literature in multiple individuals with familial hypercholesterolemia (FH) (PMIDs: 34998859 (2022), 33994402 (2021), 32041611 (2020), 28502495 (2017), 15823288 (2005), 11810272 (2001)) and myocardial infarction (PMIDs: 30971288 (2019), 25647241 (2015), 25487149 (2015)). However, in some individuals with FH or myocardial infarction, this variant is found to be associated with normal or modestly increased LDL-C levels (PMIDs: 25647241 (2015), 20506408 (2010)). A functional study characterized this variant as having an unclear effect on LDLR function and expression (PMID: 25647241 (2015)). The frequency of this variant in the general population, 0.00035 (7/19946 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hypercholesterolemia Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.E353K variant (also known as c.1057G>A), located in coding exon 7 of the LDLR gene, results from a G to A substitution at nucleotide position 1057. The glutamic acid at codon 353 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts (Fouchier SW et al. Hum Genet, 2001 Dec;109:602-15; Huijgen R et al. Hum Mutat, 2010 Jun;31:752-60; Chiou KR et al. J Clin Lipidol 2017 Jan;11:386-393.e6). This amino acid position is 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at