rs373848925
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PP3: REVEL=0.757. LINK:https://erepo.genome.network/evrepo/ui/classification/CA034649/MONDO:0007750/013
Frequency
Consequence
ENST00000558518.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LDLR | NM_000527.5 | c.1516G>A | p.Val506Met | missense_variant | 10/18 | ENST00000558518.6 | NP_000518.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LDLR | ENST00000558518.6 | c.1516G>A | p.Val506Met | missense_variant | 10/18 | 1 | NM_000527.5 | ENSP00000454071 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251450Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135908
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461872Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15AN XY: 727246
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152190Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74348
ClinVar
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1Uncertain:2Benign:1
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
Likely benign, criteria provided, single submitter | literature only | LDLR-LOVD, British Heart Foundation | Mar 25, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 27, 2024 | This missense variant replaces valine with methionine at codon 506 of the LDLR protein. This variant is also known as p.Val485Met in the mature protein. This variant alters a conserved valine residue in the LDLR type B repeat 3 of the LDLR protein (a.a. 486-528), 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 performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 20145306, 32770674, 33740630). One of these individuals also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Feb 23, 2024 | The NM_000527.5(LDLR):c.1516G>A (p.Val506Met) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence code PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 23 February 2024. The supporting evidence is as follows: PP3: REVEL=0.757. - |
Familial hypercholesterolemia Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2023 | This missense variant (also known as p.Val485Met in the mature protein) replaces valine with methionine at codon 506 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia, who also carried a large duplication variant encompassing LDLR exons 3-12 (PMID: 20145306). This variant has also been reported in another individual affected with familial hypercholesterolemia (PMID: 32770674) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 16/251450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 12, 2024 | Variant summary: LDLR c.1516G>A (p.Val506Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251450 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (6.4e-05 vs 0.0013), allowing no conclusion about variant significance. c.1516G>A has been reported in the literature in several individuals affected with Familial Hypercholesterolemia, including one who had a second LDLR variant, and it has been reported in one individual from an early myocardial infarction cohort (e.g. Chmara_2010, Do_2015, Rieck_2020, Leren_2021, Noto_2022); however these cases lacked strong evidence for causality (i.e. segregation data). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20145306, 25487149, 33740630, 35339733, 32770674). ClinVar contains an entry for this variant (Variation ID: 251881). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 11, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2018 | The p.V506M variant (also known as c.1516G>A), located in coding exon 10 of the LDLR gene, results from a G to A substitution at nucleotide position 1516. The valine at codon 506 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in one individual from an early myocardial infarction cohort, as well as in an individual with familial hypercholesterolemia (FH), who had an additional LDLR variant; however, clinical details were limited in both cases (Chmara M et al. J. Appl. Genet., 2010;51:95-106; Do R et al. Nature, 2015 Feb;518:102-6). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.007% (17/246252) total alleles studied. The highest observed frequency was 0.075% (13/17248) of East Asian alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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